CN109908099B

CN109908099B - Drug delivery system

Info

Publication number: CN109908099B
Application number: CN201910244873.XA
Authority: CN
Inventors: 约翰内斯·马蒂纳斯·马里亚·布勒默斯; 安科·科内鲁斯·艾森斯; 亨德里克·威廉·弗里亚林克; 莱昂纳德斯·赫拉尔杜斯·约瑟夫·德利德
Original assignee: EB IP HYBRITABS BV
Current assignee: EB IP HYBRITABS BV
Priority date: 2011-05-13
Filing date: 2012-05-14
Publication date: 2021-10-29
Anticipated expiration: 2032-05-14
Also published as: US20150056277A1; SG194943A1; WO2012158030A2; EA201391689A1; CN103648487A; US10966933B2; CN109908099A; NZ618535A; IL229425A0; NZ717187A; EP2709597A2; MX353623B; US20240165032A1; BR112013029199A8; JP6121990B2; JP2014513685A; AU2012256501B2; CA2835845A1; CN103648487B; US9763884B2

Abstract

The present invention relates to a drug delivery system, in particular a time controlled, immediate release drug delivery system for oral administration of a first active ingredient to a subject in need thereof. The present invention furthermore relates to a dual drug delivery device comprising a time-controlled, immediate release drug delivery system according to the present invention, further comprising a second coating comprising a second active ingredient.

Description

Drug delivery system

The application is a divisional application of Chinese patent application No. 201280034770.7 with the application date of 2012, 5, 14 and the title of 'drug delivery system'.

Technical Field

The present invention relates to the field of pharmaceutical formulations and drug delivery. More particularly, the present invention relates to time-controlled, immediate release drug delivery systems. The present invention further relates to a dual drug delivery device comprising a time controlled, immediate release drug delivery system for time controlled, immediate release of a first active ingredient and controlled release of a second active ingredient. The invention further relates to formulations for sublingual administration of active ingredients.

Pharmaceutical research is increasingly focused on intelligent drug delivery systems that improve desired therapeutic goals while reducing side effects. The present invention provides intelligent drug delivery systems for designing pharmaceutical formulations that allow controlled release, such as timed release formulations, including oral formulations.

Background

The art shows various solutions to the problem of controlled release of active ingredients. For example, diclofenac is poorly soluble in acidic media, which affects the solubility and absorption of the drug. Formulations with a delayed release mechanism, also known as enteric coating systems, prevent release of the drug in the acidic environment of the stomach while allowing release in the more favorable environment of the small intestine. Various materials, such as cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, and acrylic polymers, have been used as gastric juice resistant (gastroresistant) enteric coatings for delayed drug release in the intestine (Xu and Lee, pharm. res.10(8),1144-1152 (1993)). Enteric coating systems that are soluble at higher pH values are often used in late-stage intestinal and colon-specific delivery systems.

WO97/25979 describes a drug delivery system for targeting multiple sites of the gastrointestinal tract. The drug-containing core is coated with a hydrophobic polymer comprising hydrophilic, water-insoluble particles embedded therein. These particles act as channels for the entry of the aqueous medium of the core and for the release of the drug by diffusion through the channels.

WO99/018938 provides further examples of time-lapse drug delivery systems. WO99/018938 describes a gastrointestinal delivery system comprising a drug in combination with a swallowable core material. The core is surrounded by a water-insoluble coating material comprising a water-insoluble particulate material. When exposed to an aqueous solution, the particulate absorbs the liquid and forms channels within the coating that allow the aqueous solution to enter the core. When the core expands, the inner coating ruptures, releasing the drug from the delivery system.

Dual drug delivery devices are designed to release drugs at 2 different rates or at 2 different time periods, or to release two or more different drugs at different intervals over different time periods. Dual drug delivery devices control the release rate of one or more drugs to maximize the therapeutic effect of these drugs. Suitable drug candidates for a dual phase mode of administration include non-steroidal anti-inflammatory drugs (NSAIDs) as well as antihypertensive, antihistamine, and antiallergic ingredients. In the first phase, the drug is released rapidly to provide maximum relief in a short time frame. Followed by a sustained release phase to avoid the need for repeated frequent dosing.

Suitable devices for use as a two-stage release system are compressed bilayer tablets and "core-in-coating" systems, which involve the use of a sustained release tablet as the compressed core, which is coated over the entire surface with a disintegrating formulation. Both the core tablet and the outer coating contain a drug.

There are several two-stage release devices in the art. WO93/009771 describes dipulse flutamide tablets for the treatment of prostate cancer. The first pulse is obtained from the immediate release layer and the second pulse from the core comprising the flutamide solid dispersion in the carrier. The immediate release layer and the core are separated by a film layer of an enteric coating.

Multiparticulates also provide a two-stage release system. WO94/12160 describes a capsule containing a plurality of pills with different drug release delay times. By mixing pills of different delay times, pulsed delivery of the medicament can be obtained. The drug is contained in the pill along with the osmotic composition. The pill is coated with a water-permeable, water-insoluble film that allows water to diffuse into the pill. The osmotic agent dissolves in water causing the pill to swell and eventually burst to release the drug. The osmotic ingredients contained in the pill, and the coating of the pill, are two of the variables that determine the delay time of the drug contained in the pill.

WO 98/51287 describes a pulsing system based on a plurality of particles in a dosage form. The release of drug from the granules is controlled by the combination of the controlled release layer, the expansion layer and the coating layer. The controlled release layer is a high molecular weight crosslinked poly (acrylic acid) polymer mixed with a water soluble polymer.

WO00/074655 provides a further drug delivery device, the system of which is based on the drug delivery system provided in WO 97/25979. Furthermore the inner coating of the drug delivery system is surrounded by an outer coating comprising an additional amount of the desired ingredient. When the delivery device enters the gastrointestinal tract, the outer coating releases the desired ingredients contained therein and disintegrates, exposing the inner coating. The location of release of the two drug pulses can be controlled by controlling parameters in the device, such as the core material, the carrier material in the coating, and the particulate matter.

The above drug delivery systems, while effective at delaying drug release to a particular site in the gastrointestinal tract such as, for example, the small intestine or colon, have been found to be ineffective at providing the drug in short bursts after a certain period of time, whether or not present in a particular body compartment.

There is a clear need for a drug delivery system that releases the drug after a predetermined period of time (lag time) after administration of the drug delivery system. Furthermore, there is a need for a drug delivery device that combines a drug delivery system that is effective in delivering a drug in short pulses after a predetermined period of time and a drug delivery system that provides immediate release of the drug at an earlier point in time after administration, preferably in the oral cavity.

Disclosure of Invention

Accordingly, the present invention provides a time-controlled, immediate release drug delivery system for oral administration of a therapeutically effective amount of a first active ingredient to a subject in need thereof, comprising a disintegrating core comprising cellulose, a filler selected from organic and/or inorganic salts, and the first active ingredient, the system further comprising a first coating surrounding the core, the first coating comprising an outer surface, the first coating further comprising a hydrophobic polymer and a water-soluble and/or water-insoluble hydrophilic substance.

The core according to the invention comprises

A first active ingredient, the relative amount of which is preferably between 0.1% and 60% (w/w; based on the total weight of the core), more preferably between 0.1% and 30% (w/w; based on the total weight of the core), more preferably between 5% and 25% (w/w; based on the total weight of the core),

cellulose, the relative amount of which is preferably between 10% and 60% (w/w; based on the total weight of the core), more preferably between 10% and 50% (w/w; based on the total weight of the core), and

the relative amount of filler selected from organic and/or inorganic salts is preferably between 10% and 70% (w/w; based on the total weight of the core), more preferably between 10% and 60% (w/w; based on the total weight of the core).

Throughout this specification, the term "comprising" and its grammatical equivalents means that the listed components are present and that other components may or may not be present. The term "comprising" preferably has the meaning of "consisting of only … …".

The core is preferably extruded or compacted into a solid. The preferred core is a tablet. The term "tablet" encompasses "capsule" and "caplet". Preferred dimensions of the core of the drug delivery system according to the invention range from a few millimetres to about one centimetre. Additional excipients may include diluents, binders or granulating ingredients, carbohydrates such as starch, starch derivatives (e.g., starch acetate and/or maltodextrin), polyols (e.g., xylitol, sorbitol and/or mannitol), lactose (e.g., alpha-lactose monohydrate, anhydrous alpha-lactose, anhydrous beta-lactose, spray-dried lactose, and/or agglomerated lactose), sugars (e.g., glucose, maltose, dextrates (and/or inulin), or combinations thereof, glidants (flow aids) and lubricants to ensure high compression, and sweeteners or flavoring agents to improve mouthfeel.

The first active ingredient may be a single active ingredient, or a mixture of two or more active ingredients. Preferably, each active ingredient is present in a relative amount of between 0.1% and 30% (w/w), more preferably between 5% and 25% (w/w) in the mixture of active ingredients.

Preferred time-controlled, immediate release drug delivery systems according to the present invention comprise immediate release formulations comprising a compressed core comprising one or more active ingredients surrounded by a coating, wherein the release of the active ingredient from the core is caused by rupture of the coating after a predefined lag time. Preferably, the core disintegrates immediately after the coating is broken or dissolved.

The term cellulose includes powdered cellulose, agglomerated cellulose, microcrystalline cellulose, and/or combinations thereof. The term cellulose includes purified cellulose, methyl cellulose, hydroxypropyl methyl cellulose, and carboxymethyl cellulose. Powdered cellulose mainly consists of cellulose obtained by breaking down pulp. Microcrystalline cellulose includes certain grades of alpha cellulose.

The preferred cellulose is microcrystalline cellulose. Preferred microcrystalline cellulose has a nominal particle size between 30 μm and 250 μm, preferably between 50 μm and 180 μm. Further preferred microcrystalline cellulose contains from 0.1% to 7.5%, more preferably from 1% to 5.0% moisture. Preferred microcrystalline celluloses are selected from microcrystalline celluloses having a nominal particle size of 50 μm and 3.0% to 5.0% moisture such as, for example, Avicel PH 101; microcrystalline cellulose having a nominal particle size of 100 μm and 3.0% to 5.0% moisture such as, for example, Avicel PH 102; and microcrystalline cellulose having a nominal particle size of 180 μm and less than 1.5% moisture such as, for example, Avicel PH 200. The amount of microcrystalline cellulose is preferably greater than 10% (w/w; based on the total weight of the core), more preferably greater than 20% (w/w), more preferably greater than 30%, most preferably greater than about 35%. It is further preferred that the amount of microcrystalline cellulose is less than 60%, more preferably less than 50%, more preferably less than 45% (w/w, based on the total weight of the core).

Preferred cores according to the invention comprise fillers. The filler is preferably present in an amount of between 10% and 70% (w/w; based on the total weight of the core), more preferably between 20% and 60% (w/w), more preferably between 30% and 50% (w/w), such as 35% (w/w). The filler is selected from the group of organic and inorganic salts. The organic salt is preferably selected from the group consisting of calcium citrate, magnesium citrate, calcium lactate, sodium lactate, magnesium lactate, calcium fumarate and magnesium fumarate. The most preferred fillers are inorganic salts. The inorganic salt according to the invention is preferably selected from the group consisting of calcium sulfate dehydrate, calcium silicate, silicon phosphate, calcium carbonate, calcium hydrogen phosphate anhydrous, calcium hydrogen phosphate monohydrate, tricalcium phosphate, sodium chloride, potassium phosphate, potassium sulfate, potassium chloride, sodium carbonate, magnesium carbonate, and magnesium oxide. The total amount of soluble fillers such as sodium lactate and sodium chloride is preferably below 50% (w/w; based on the total weight of the core). The choice of filler is further determined by the intrinsic stability of the active ingredient in the core in combination with one filler or in combination with a plurality of fillers, as is known to the person skilled in the art. The core may further include lubricating agents such as magnesium stearate, talc, and the like. Preferred cores include anhydrous dibasic calcium phosphate and magnesium stearate. The amount of anhydrous dibasic calcium phosphate is preferably greater than 10% (w/w; based on the total weight of the core), more preferably greater than 20% (w/w), more preferably greater than 30%, most preferably greater than about 35%. It is further preferred that the amount of anhydrous dibasic calcium phosphate is less than 70%, more preferably less than 60%, more preferably less than 50%, more preferably less than 45% (w/w, based on the total weight of the core). The amount of magnesium stearate is preferably between 0.1% (w/w; based on the total weight of the core) and 10% (w/w), more preferably between 0.5% and 5% (w/w).

The core may additionally include one or more disintegrants that form a gel when exposed to an aqueous solution as a neat substance. Preferred disintegrants include one or more of the gel-forming (gel-forming) disintegrants that are water insoluble. When present, the disintegrant, such as a water-insoluble gel-forming disintegrant, is preferably present in a relative amount of between 0.5% and 20% (w/w). Disintegrants are substances or mixtures of substances that facilitate the breaking or disintegration of a tablet. The breaking of the tablet produces smaller particles whose ingredients, including the first active ingredient, are available for ingestion faster than the entire tablet. By adding a disintegrating ingredient to the formulation, drug solubility can be significantly improved. Preferred disintegrants induce tablet disintegration by wicking, deformation, and/or the induction of interparticle electrical repulsion.

Preferred disintegrants according to the invention are selected from sodium starch glycolate

Sodium croscarmellose (e.g.,

) Crosslinked polyvinylpyrrolidone (crospovidone), and a polyvinylpyrrolidone having a hydroxypropyl content ranging from 5.0% to 16.0% by weight and an apparent value ranging from 350 to 700Low-substituted hydroxypropylcellulose (L-HPC) having an average degree of polymerization. The L-HPC preferably has a low particle size, preferably an average particle size of less than 10 microns, more preferably less than 5 microns such as, for example, LH 41. The water-insoluble gel-forming disintegrant is preferably present in a relative amount of between 0.0% and 6% (w/w). The amount of said water-insoluble gel-forming disintegrant is preferably less than 6% (w/w; based on the total weight of the core), more preferably less than 5% (w/w), most preferably less than 4%.

Preferred compositions of the core according to the invention comprise a first active ingredient, microcrystalline cellulose (e.g.,

pH102 or

pH200), dibasic calcium phosphate anhydrous, croscarmellose sodium (e.g., croscarmellose), and magnesium stearate. The microcrystalline cellulose and croscarmellose sodium are preferably present in a ratio of between about 6:1(w/w) to 14:1(w/w), preferably between 7.5(w/w) to 12.5 (w/w). Preferred ratios are about 10:1(w/w) and about 8:1 (w/w). The effect of this ratio is that the core does not substantially swell before disintegration at the time of gel formation. The preferred ratio of anhydrous dibasic calcium phosphate and microcrystalline cellulose is between 3:1(w/w) and 1:3(w/w), more preferably between 2:1(w/w) and 1:2(w/w), most preferably about 1:1 (w/w).

The total weight of the core according to the invention is preferably between 50mg and 500 mg, more preferably between 200mg and 400 mg, more preferably between 300mg and 400 mg, such as about 340 mg.

The core according to the invention is surrounded by a first coating comprising an outer surface, said first coating further comprising a hydrophobic polymer and a (water-soluble and/or water-insoluble) hydrophilic substance. The first coating preferably does not include a drug. When present, plasticizers such as, for example, dibutyl phthalate, triethyl citrate, acetyl triethyl citrate, dibutyl sebacate, diethyl phthalate, triacetin and/or tributyl citrate, are preferably present in an amount of up to 0.5% (w/w; based on the total weight of the time-controlled, immediate release drug delivery system). The first coating preferably does not comprise a plasticizer.

The first coating is preferably sprayed onto the core, e.g. using a nozzle. For this purpose, the hydrophobic polymer and the water-soluble and/or water-insoluble hydrophilic substance are suspended or dissolved, for example in water or an organic solvent or a mixture thereof, and sprayed onto the core until a predetermined average thickness of the first coating is obtained. Preferred organic solvents are alcohols, for example, ethanol. The amount of the first coating is preferably between about 0.5% to 30% (w/w), more preferably between about 1% to 20% (w/w) of the total weight of the time-controlled, immediate release drug delivery system.

The hydrophobic coating polymer according to the invention is preferably selected from water-insoluble coating materials such as cellulose derivatives and polymethacrylates produced by copolymerization of e.g. methacrylate monomers with hydrophobic groups. Preferred polymethacrylate hydrophobic polymers are

RL、

RS、

NE, and

S。

preferred cellulose derivatives are selected from ethyl cellulose and derivatives thereof. The most preferred hydrophobic polymer of the first coating of the drug delivery system according to the present invention comprises ethylcellulose. Ethyl cellulose forms a mechanically weakly hydrophobic film that is easily broken. The core contains the drug in combination with a disintegrant formed from a water-insoluble gel that disintegrates upon contact with aqueous media. Pores were formed in the hydrophobic film and water flowed into the core, causing rupture of the ethylcellulose coating. Upon rupture of the coating, the core disintegrates within a few minutes, after which the drug is released. Preferred ethyl cellulose is

The hydrophilic substance according to the invention is preferably a water-insoluble hydrophilic substance, preferably a water-insoluble hydrophilic polymer. It is further preferred that the first coating comprises pores prior to exposure to the aqueous solution. The pores serve as channels interconnecting the core and the outer surface of the inner coating for controlling the ingress of aqueous solution into the core. For example, the pores are present when the water-insoluble hydrophilic substance is or comprises a water-insoluble hydrophilic polymer (preferably cellulose). Preferred celluloses are cellulose derivatives such as, for example, hydroxypropyl cellulose, cross-linked hydroxyethyl cellulose, cross-linked hydroxypropyl methylcellulose and microcrystalline cellulose. The cellulose forms a channel connecting the drug-containing core with the outside of the tablet. So that the cellulose controls the rate of water transport through the channels into the core. When sufficient water reaches the core, the core relaxes its structural integrity. The core will disintegrate, followed by rupture of the coating and release of the drug. Preferred celluloses are microcrystalline celluloses having a nominal particle size between 20 and 200 microns and less than 5% moisture. Preferred microcrystalline celluloses include microcrystalline celluloses having a nominal particle size of about 150 microns and 3.0% to 5.0% moisture such as, for example,

PH-102 SCG; microcrystalline cellulose having a nominal particle size of about 100 microns and less than 5.0% moisture such as, for example,

HFE-102; and microcrystalline cellulose having a nominal particle size of about 20 microns and less than 5.0% moisture such as, for example,

the pH value is-105. Further preferred water insoluble hydrophilic substances include dicalcium phosphate.

Smaller particles smaller than 50 microns are used (e.g.,

PH-105) has the advantage that the coating suspension has better flow properties, which improves the overall film coating process. Preferably the first coating comprises

And Avicel PH-105 as a hydrophilic substance insoluble in water. Hydrophobic coating polymers (e.g. of the type

) Preferred mass ratios to the water-insoluble hydrophilic species (e.g. Avicel) are between 1:5 and 5:1, more preferably between 1:4 and 3:1, more preferably between 1:3 and 2:1, most preferably about 1: 2.

In another embodiment, the hydrophilic substance according to the invention is preferably a water-soluble hydrophilic substance. Such a coating preferably comprises no pores or only a few pores before exposure to the aqueous solution. Preferably, the water-soluble hydrophilic species forms pores in the hydrophobic polymer upon exposure to an aqueous solution. Preferred water-soluble hydrophilic substances include lactose, mannitol and/or sodium chloride. The preferred lactose is

Preferably the first coating comprises

And lactose as a water-soluble hydrophilic substance. Hydrophobic coating polymers (e.g. of the type

) Preferred mass ratios to water soluble hydrophilic substances (e.g. lactose) are between 1:5 and 5:1, more preferably between 1:3 and 3:1, more preferably between 1:2 and 2:1, most preferably about 1: 1.

The relative amount of the first coating is preferably between 4% and 20% (w/w; based on the total weight of the drug delivery system), more preferably between 8% and 15% (w/w), most preferably about 12% (w/w). Thus, preferred first coatings have a weight of between 10mg and 75mg, more preferably between 25mg and 50mg, most preferably about 40 mg.

The time controlled, immediate release drug delivery system according to the present invention allows for a controlled release of the first active ingredient after hydration of the drug delivery system. The time-controlled, immediate release is substantially independent of pH. The time period is controlled in part by the thickness of the first coating, which is preferably sprayed onto the core. The amount of the first coating between tablets preferably varies by no more than 10% (between 90% and 110%) based on the total weight of the first coating. More preferably, the amount of the first coating does not vary by more than 5% (between 95% and 105%) based on the total weight of the first coating. Factors (process conditions) that may affect intra-or inter-tablet uniformity of the first coating include spray rate, spray pattern, nozzle type, viscosity, drying temperature, air flow rate, and coating time as known to those skilled in the art. If desired, a temperature controlled curing step is applied to the first coating after application (preferably spraying) of the first coating, for example, a heat treatment at 60 ℃ to 80 ℃ for 1 hour to 3 hours.

Furthermore, the amount of water-soluble and/or water-insoluble hydrophilic substance in the first coating, and the nature of the water-soluble and/or water-insoluble hydrophilic substance, further provides a means to modulate the timed release of the first active ingredient. For example, a tablet comprising a compressed core and a first coating having an average thickness of about 35 microns comprising ethylcellulose 20 and lactose in a ratio of 3:2 provides release of the first active ingredient at about 36 minutes after hydration of the tablet, while the same composition of a tablet having a first coating having an average thickness of about 50 microns provides release of the first active ingredient at about 84 minutes after hydration of the tablet. A tablet comprising a compressed core and a first coating having an average thickness of about 90 microns comprising ethylcellulose 20 and Avicel PH102 in a ratio of 3:2 provides release of the first active ingredient at about 105 minutes after hydration of the tablet. Based on the teachings and examples provided in this application, the skilled person is able to produce a time controlled, immediate release drug delivery system according to the present invention.

The total weight of the drug delivery device according to the present invention is preferably at least 50mg, more preferably at least 150mg, and preferably between 50mg and 500 mg, more preferably between 150mg and 400 mg, more preferably between 300mg and 400 mg, such as about 301.5 mg, 325 mg, or about 340 mg.

The time-controlled drug delivery system according to the present invention provides a release of the first active ingredient after about a predetermined period of time (lag time), such as after about 1 hour after administration of the drug delivery system, more preferably after about 1.5 hours, more preferably after about 2 hours, more preferably after about 2.5 hours, more preferably after about 3 hours, more preferably after about 3.5 hours, more preferably after about 4 hours, more preferably after about 4.5 hours, more preferably after about 5 hours, more preferably after about 6 hours, more preferably after about 7 hours, more preferably after about 8 hours, more preferably after about 10 hours.

The term "time-controlled" drug delivery system refers to a drug delivery system that provides release of the first active ingredient after a predetermined period of time (e.g., 2 hours), wherein the release is independent of pH. The predetermined period of time is set and is independent of the pH history in the gastrointestinal tract.

The term "immediate release" drug delivery system refers to a drug delivery system that provides for a substantial release of the first active ingredient after a predetermined period of time. For example, an immediate release drug delivery system provides greater than 60%, more preferably greater than 70%, more preferably greater than 80% release of the first active ingredient within 30 minutes after the coating is ruptured, more preferably within 20 minutes after the coating is ruptured, more preferably within 8 minutes after the coating is ruptured. Methods and devices (e.g., as a method of determining dissolution) for determining the amount of first active ingredient released from a drug delivery system and the time frame of ingredient release are known to the skilled person, e.g., the United States Pharmacopeia (USP) based on dissolution tests in device 2 (paddle method) and device 3 (shuttle cartridge).

The immediate release of the first active ingredient is believed to be caused by moisture-induced stress relaxation. The driving force for this stress relaxation is the amount of energy stored within the core surrounded by the polymer coating (Van der Voort Maarschalk et al, 1997.Int J pharmaceuticals 151: 27-34; Van der Voort Maarschalk et al, 1997.Pharm Res 14: 415-419; Steendam et al, 2001.J Control Rel 70: 71-82; Laity and Cameron,2010.Eur J Pharm Biopharm 75: 263-276). Stress relaxation mediates the rupture of the coated core according to the invention in a nonlinear manner. Hydration of the core with the hydrophilic substance in the first coating mediates stress relaxation such that an immediate rupture of the coating is obtained after a predetermined period of time. It was found that the presence of more than 6% (w/w) of the water-insoluble gel-forming disintegrant interfered with the immediate release of the first active ingredient and resulted in a more sustained release profile.

The term "first active ingredient" refers to an ingredient present in the core. The first active ingredient may be a single active ingredient, or a mixture of two or more active ingredients. The first active ingredient present in the core of the drug delivery system according to the invention may be any ingredient which is preferably released after a defined period of time. Examples of active ingredients that are preferably released at a defined time after administration (e.g. in the morning) are anti-asthmatics (e.g. bronchodilators), anti-emetics, cardiotonics, vasodilators, anti-vertigo and anti-meniere agents, anti-ulcer agents, corticosteroids such as prednisone, other anti-inflammatory agents, analgesics, anti-rheumatic agents, anti-arthritic agents; anti-anginal drugs; and antihypertensive agents. In addition, such formulations may be very useful for other compounds to improve patient compliance, including sedatives such as neuroleptics, antidepressants, and other CNS compounds.

Other kinds of active ingredients that are preferably formulated in the drug delivery system according to the invention are biologically active proteins, peptides, enzymes, vaccines and oligonucleotides. Many times these types of compounds are not resistant to the acidic environment of the stomach.

A still further preferred type of active ingredient which is preferably formulated in the drug delivery system according to the invention is an ingredient which is preferably administered in a two-phase release mode. The formulations of the invention are particularly amenable to antibiotics such as penicillins, cephalosporins, and benzodiazepines

The administration of quasi-drugs, calcium antagonists and short-acting hypnotics.

A further preferred type of active ingredient which is preferably formulated in the drug delivery system according to the invention is a drug which is part of a pharmaceutical combination of at least two different active ingredients. Embodiments of these types of active ingredients are combinations of active ingredients whereby the first active ingredient mitigates the negative effects of the second active ingredient or promotes/enhances the effects of the second active ingredient. Examples are second active ingredients which cause side effects such as, for example, constipation, nausea, gas/bloating, burning, pain or cramping. The first active ingredient is provided before the second active ingredient. The first active ingredient alleviates the above side effects of the second active ingredient, for example, providing laxative drugs, nausea treatment drugs, anti-gas and anti-swelling drugs, antacid drug therapy, analgesic & muscle relaxant drugs.

The first active ingredient provides a still further preferred example, the first active ingredient being combined after the time required for the action of the first ingredient with a second active ingredient which controls and stops the action of the first ingredient. For example, using the drug delivery system according to the present invention, it may be advantageous to deliver a combination of an immediate release anticancer drug, such as methotrexate, and a time-controlled release "breaker" component, such as L-formyltetrahydrofolate. In all these examples, the second active ingredient is preferably formulated in a drug delivery system according to the present invention.

An active ingredient which acts synergistically with another active ingredient in the same affected area, but is released at a different time than the other active ingredients, and/or has to be administered in different areas in the oral cavity and/or the gastrointestinal tract, provides an even more preferred type of active ingredient which is preferably formulated in the drug delivery system according to the invention.

The most preferred examples are preferred for treating males or females: a combination therapy for sexual dysfunction, sexual desire dysfunction, or erectile dysfunction. Preferably, the combination therapy is the treatment of hypoactive sexual desire disorder. Preferably, a combination of testosterone or a functional analogue thereof and the first active ingredient is used, whereby testosterone or a functional analogue thereof is provided such that a peak plasma level of testosterone occurs about 2-6 hours, more preferably 3-4 hours before a peak plasma level of the first active ingredient. The first active ingredient is preferably provided in a time-controlled, immediate release drug delivery system according to the present invention.

Preferably the treatment is for males or females: preferred first active ingredients for sexual dysfunction, sexual desire dysfunction, erectile dysfunction and preferably for the treatment of hypoactive sexual desire disorder are selected from the group consisting of PDE5 inhibitors, inhibitors of Neutral Endopeptidase (NEP) and 5-hydroxytryptamine 1A receptor agonists (5-HT1 Ara). The PDE5 inhibitor is preferably selected from vardenafil, sildenafil and tadalafil or any other known PDE5 inhibitor. Further non-limiting examples of PDE5 inhibitors are: e-4021, E-8010, E-4010, AWD-12-217 (minoxidil), AWD12-210, UK-343,664, UK-369003, UK-357903, BMS-341400, BMS-223131, FR226807, FR-229934, EMR-6203, Sch-51866, IC485, TA-1790 (Avanafil), DA-8159 (Udenafil), NCX-911 or KS-505 a. Other examples can be found in WO 96/26940. Vardenafil HCl provides a typical example for oral administration of vardenafil, which is chemically known as 1- [ [3- (1, 4-dihydro-5-methyl-4-oxo-7-propylimidazo [5,1-/] [ l,2,4] triazin-2-yl) -4-ethoxyphenyl ] sulfonyl ] -4-ethyl-piperazine monohydrochloride. Another example is given in sildenafil citrate, which is chemically known as 1- [ [3- (6, 7-dihydro-l-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d ] pyrimidin-5-yl) -4-ethoxyphenyl ] sulfonyl ] -4-methylpiperazine citrate.

A preferred PDE5 inhibitor according to the invention is sildenafil, which is preferably administered as sildenafil citrate (l- [ [3- (6, 7-dihydro-l-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d ] pyrimidin-5-yl) -4-ethoxyphenyl ] sulfonyl ] -4-methylpiperazine citrate).

For treating male or female: the first active ingredient, which is sexual dysfunction, sexual desire dysfunction, erectile dysfunction and which is preferably further preferred for the treatment of hypoactive sexual desire disorder, is an inhibitor of Neutral Endopeptidase (NEP).

Preferred NEP inhibitors are selected from amongst candesartan; candela; deecadotril ((+) -N- [ 2(R)) - (acetylthiomethyl) -3-phenylpropionyl]Benzyl glycine ester; CGS-24128(3- [3- (biphenyl-4-yl) -2- (phosphonomethyl amino) propionamido]Propionic acid); CGS-245792 ((S) -3- [3- (biphenyl-4-yl) -2- (phosphonomethyl amino) propionamido]Propionic acid); CGS-25155(N- [9(R) - (acetylthiomethyl) -10-oxo-1-azacyclodec-2 (S) -ylcarbonyl)]-4(R) -hydroxy-L-proline benzyl ester); 3- (1-carbamoylcyclohexyl) propionic acid derivatives as described in WO 2006/027680; JMV-390-1(2(R) -benzyl-3- (N-hydroxycarbamoyl) propionyl-L-isoleucyl-L-leucine); ecadotril; amiloride phosphate; trithio-oxophenpropyl glycine (retrothiorphan); RU-42827(2- (mercaptomethyl) -N- (4-pyridyl) phenylacrylamide); RU-44004(N- (4-morpholinyl) -3-phenyl-2- (thiomethyl) propionamide); SCH-32615((S) -N- [ N- (1-carboxy-2-phenylethyl) -L-phenylalanyl]-3-alanine) and its prodrug SCH-34826((S) -N- [1- [ [ (2, 2-dimethyl-1, 3-dioxalan-4-yl) methoxy]Carbonyl radical]-2-phenylethyl group]-L-phenylalanyl]-3-alanine); salprofen; SCH-42495(N- [2(S) - (acetylthiomethyl) -3- (2-methylphenyl) propionyl group]-ethyl-L-methionine); silibinofen; SQ-28132(N- [2- (mercaptomethyl) -1-oxo-3-phenylpropyl)]Leucine); SQ-28603(N- [2- (mercaptomethyl) -1-oxo-3-phenylpropyl)]-3-alanine); SQ-29072(7- [ [2- (mercaptomethyl) -1-oxo-3-phenylpropyl)]Amino group]Heptanoic acid); seofine and its prodrug racecadotril; UK-69578 (cis-4- [ [ [1- [ 2-carboxy-3- (2-methoxyethoxy) propyl ] ethyl)]Cyclopentyl group]Carbonyl radical]Amino group]Cyclohexane carboxylic acid); UK-447,841(2- {1- [3- (4-chlorophenyl) propylcarbamoyl)]-cyclopentylmethyl } -4-methoxybutyric acid); UK-505,749((R) -2-methyl-3- {1- [3- (2-methylbenzothiazol-6-yl) propylcarbamoyl)]Cyclopentyl } propanoic acid); 5-biphenyl-4-yl-4- (3-carboxypropionylamino) -2-methylpentanoic acid and ethyl 5-biphenyl-4-yl-4- (3-carboxypropionylamino) -2-methylpentanoate (WO 2007/056546); dacrolutril [ (3S,2' R) -3- {1- [2' - (ethoxycarbonyl) -4' -phenylbutyl ] described in WO2007/106708]-cyclopentyl-1-carbonylamino } -2,3,4, 5-tetrahydro-2-oxo-1H-1-benzazepine

-1-ethylAcid(s)](ii) a And combinations thereof.

Preferred NEP inhibitors according to the invention are selective for NEP compared to soluble Secreted Endopeptidase (SEP). NEP breaks down a hormone called Vasoactive Intestinal Peptide (VIP) which promotes blood flow to the vagina. Neuropeptides such as Vasoactive Intestinal Peptide (VIP) are the major neurotransmitter in the control of genital blood flow. VIP and other neuropeptides are degraded/metabolized by NEP. Thus, NEP inhibitors will potentiate the endogenous vasodilatory action of VIP released during sexual arousal. This can cause increased genital blood flow and thus congestion of the genitals. Selective inhibitors of NEP enhance pelvic nerve-stimulated and VIP-induced increases in vaginal and clitoral blood flow. In addition, selective NEP inhibitors enhance VIP and neuro-mediated relaxation of the detached vaginal wall. Thus, the effects of NEP inhibitors are similar to those of PDE5 inhibitors, i.e., increased vaginal and clitoral blood flow. Preferred NEP inhibitors are UK-447,841 and UK-505,749.

Preferably for treating male or female: a further preferred first active ingredient for sexual dysfunction, sexual desire dysfunction, erectile dysfunction and preferably for the treatment of hypoactive sexual desire disorder is a 5-hydroxytryptamine 1A receptor agonist (5-HT1 Ara). Preferably, 5-HT1Ara is selective for the 5-HT1A receptor as compared to other 5-HT receptors as well as alpha-adrenergic receptors and dopamine receptors. Non-limiting examples of 5-HT1Ara are 8-OH-DPAT, anespirinone, AP-521, busapar (Buspar), buspirone, dipropyl-5-CT, DU-125530, E6265, ibandrotan, etapirone, fluorosinxon, flibanserin, gepirone, ixapiron, lesopitron, LY293284, LY301317, MKC242, R (+) -UH-301, rapitant, SR57746A, sulindac, SUN-N4057, tandospirone, U-92016A, urapidil, VML-670, zaspirone, and ziprasidone. A preferred 5HT1A receptor agonist is buspirone.

It is further preferred that the first active ingredient in the time-controlled, immediate release drug delivery system according to the invention is a combination of two or more active ingredients, such as but not limited to two or more PDE5 inhibitors, two or more NEP inhibitors, a combination of two or more 5-HT1A receptor agonists, or a combination of at least one PDE5 inhibitor and at least one NEP inhibitor, a combination of at least one PDE5 inhibitor and at least one 5-HT1A receptor agonist, a combination of at least one NEP inhibitor and at least one 5-HT1A receptor agonist, and a combination of at least one PDE5 inhibitor, at least one NEP inhibitor and at least one 5-HT1A receptor agonist.

The present invention further provides a dual drug delivery device comprising a time-controlled, immediate release drug delivery system according to the present invention, wherein the first coating of the time-controlled, immediate release drug delivery system is surrounded by a second coating comprising a second active ingredient.

The second coating provides release of the second active ingredient in an immediate release manner or a controlled release manner. The second coating may be pressed or sprayed onto the outer surface of the first coating. Methods for pressing or spraying are known in the art. The second coating surrounding the first coating advantageously protects the integrity of the first coating, such as during packaging or storage of the dual drug delivery device. This will preferably reduce or minimize the damage of the first coating that occurs during packaging or storage, which may affect the lag time of the release of the first active ingredient from the core of the dual drug delivery device.

The second coating is preferably sprayed onto the outer surface of the first coating. When a spray coating is used, it is generally formulated to contain the drug and film-forming ingredients so that the drug is dispersed in the film of the first coating covering the core. Such film forming ingredients are known in the art and may be, for example, hydroxypropylmethyl cellulose, povidone, hydroxyethyl cellulose, other modified celluloses known in the art, polyacrylates, polymethacrylates, and polymethylmethacrylate/ethyl esters. The film forming ingredient according to the present invention preferably comprises hydroxypropyl methylcellulose, more preferably low molecular weight hydroxypropyl methylcellulose having a number average molecular weight of less than 20,000; more preferably below 10,000.

The spray coating may be formulated to provide short term sustained release by forming a slow dissolving coating or to provide immediate release by forming a fast dissolving coating. The amount of film-forming ingredient is preferably between 0.05% (w/w) and 40% (w/w), more preferably between 1% (w/w) and 30% (w/w), such as, for example, about 20% (w/w), based on the total weight of the second coating.

The second coating preferably comprises a weight between 0.5% (w/w) and 5% (w/w), based on the total weight of the drug delivery device. Preferably, the coating comprises a weight between 1% and 3% and preferably between 1.5% and 2.5% (w/w), based on the total weight of the drug delivery device. In a preferred embodiment, the second coating of the drug delivery system comprises a weight between about 1 mg/unit and 20 mg/unit. Preferably, the second coating comprises a weight of about 3 mg/unit to 15 mg/unit. In a particularly preferred embodiment, said second coating of the drug delivery device of the present invention comprises a weight of about 4 mg/unit to 10 mg/unit.

The second coating of the dual drug delivery device according to the present invention preferably comprises a second active ingredient. Thus, the amount of the second coating sprayed onto the outer surface of the first coating determines the amount of the second active ingredient in the dual drug delivery device. It is therefore necessary to control the amount of the second coating. The amount of the second coating between tablets preferably varies by no more than 10% (between 90% and 110%) based on the total weight of the second coating. More preferably, the amount of the second coating varies by no more than 5% (between 95% and 105%) based on the total weight of the second coating. Factors (process conditions) that may affect intra-or inter-tablet uniformity of the second coating include spray rate, spray pattern, nozzle type, viscosity, drying temperature, air flow rate, and coating time as known to those skilled in the art. The amount of the second active ingredient is preferably between 0.05% (w/w) and 20% (w/w), more preferably between 0.5% (w/w) and 10% (w/w), based on the total weight of the second coating.

Examples of known excipients that may be added to the sprayed or compressed second coating for controlled release are one or more polymers or copolymers selected from the group consisting of: acrylic and methacrylic acid polymers and copolymers such as acrylic and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylate, cyanoethyl methacrylate, poly (acrylic acid), poly (methacrylic acid), alkyl amide methacrylate copolymers, poly (methyl methacrylate), polymethacrylates, poly (methyl methacrylate) copolymers, polyacrylamides, aminoalkyl methacrylate copolymers, poly (methacrylic anhydride), glycidyl methacrylate copolymers and ethylcellulose. The amount of known excipients is preferably below 10% (w/w), more preferably below 5% (w/w), more preferably below 1% (w/w), based on the total weight of the second coating.

The second coating of the dual drug delivery device according to the present invention preferably provides for immediate delivery of the second active ingredient in the mouth. The term "mouth" includes the space between the lips and the teeth, the space between the cheeks and the teeth, the oral cavity defined by the palate and tongue, and the sublingual area. The second active ingredient is preferably released in the sublingual space in the mouth.

The term "immediate release of the second active ingredient" means that the second coating dissolves rapidly in the mouth, such that the second active ingredient is completely or substantially completely released in the mouth within a short time frame. The term "immediate release of the second component" means that at least 50% of the second active ingredient is released within 5 minutes, more preferably within 4 minutes, more preferably within 2 minutes, most preferably within 1 minute after oral administration of the dual drug delivery device. More preferably, at least 70% of the second active ingredient is released within 5 minutes, more preferably within 4 minutes, more preferably within 2 minutes, most preferably within 1 minute after oral administration of the dual drug delivery device.

An advantage of the dual drug delivery device according to the present invention is that food action is minimized. The term "food effect" refers to the difference in the rate and extent of absorption of a drug taken immediately after a meal (fed condition) as compared to administration in fasting conditions. The release of the first active ingredient is independent of pH and therefore cannot be affected by food action. In addition, the formulation of the second active ingredient as an immediate release formulation also minimizes the food effect on the release of the second active ingredient.

A further advantage of the dual drug delivery device according to the present invention is that it provides two separate routes of administration in one tablet.

A further advantage of the dual drug delivery device according to the present invention is that it provides a first-pass absorption (first-pass absorption) of one active ingredient (herein defined as the second active ingredient) into the systemic circulation in combination with a gastrointestinal absorption of another active ingredient (herein defined as the first active ingredient) in one tablet.

A further advantage of the dual drug delivery device according to the present invention is that it provides sublingual absorption of one active ingredient (defined herein as the second active ingredient) in combination with gastrointestinal absorption of another active ingredient (defined herein as the active ingredient) into the systemic circulation in one tablet.

The second active ingredient may or may not be similar to the first active ingredient. In one embodiment, the second active ingredient, e.g. a steroid such as testosterone, is provided sublingually by the dual drug delivery device according to the invention in the absence of the first active ingredient. In this embodiment, the core of the dual drug delivery device does not comprise an active ingredient.

The second active ingredient is preferably dissimilar to the first active ingredient. A further advantage of the dual drug delivery device according to the present invention when the second active ingredient is not similar to the first active ingredient is that the timed release of the first and second active ingredients avoids interactions that may occur between the first and second active ingredients.

Examples of the second active ingredient are methotrexate, which is provided in an immediate release formulation, and L-leucovorin, which is provided as an "interruptor" in a time-controlled, immediate release formulation.

The sparingly soluble second active ingredient can be effectively absorbed from the mouth in the presence of the carrier. For poorly soluble active ingredients (e.g. steroids such as testosterone, progesterone and estradiol, NSAIDS, cardiac glycosides, antidiabetics or benzodiazepines)

Class) ofSuitable carriers include cyclodextrins, derivatives thereof, or mixtures of derivatives of cyclodextrin monomers or polymers thereof. Derivatives of cyclodextrins are chemical modifications of cyclodextrins at the hydroxyl sites. Cyclodextrin polymers are chemical derivatives in which a plurality of cyclodextrin monomers or derivatives are covalently bound. Oral administration of drugs complexed with cyclodextrins or their derivatives allows the hormone to be efficiently absorbed and enter the systemic circulation, then to be gradually eliminated, thus avoiding rapid first-pass losses. Suitable cyclodextrins are, for example, hydroxypropyl-beta-cyclodextrin, poly-beta-cyclodextrin and gamma-cyclodextrin, methyl-cyclodextrin and acetonylpropylhydroxypropyl-cyclodextrin.

Estradiol or an analogue or derivative thereof (e.g. for the treatment of osteoporosis) provides a further example of a second active ingredient in a dual drug delivery device according to the invention. The estradiol or the analogue thereof may have one or more additional drugs used as a first active ingredient in the treatment of osteoporosis. Examples of such additional drugs are calcium modulators such as alendronate, clodronate, etidronate, pamadronate, risedronate, tiludronate and/or ibandronate; calcium salts such as, for example, calcium phosphate and/or calcium carbonate; and/or vitamin D derivatives such as, for example, cholecalciferol, calcitriol and/or alfacalcidol. The estradiol, or an analogue or derivative thereof, may be replaced by a Selective Estrogen Receptor Modulator (SERM) (e.g., raloxifene) or by a parathyroid hormone (e.g., a recombinant parathyroid hormone such as teriparatide) as a second active ingredient. As indicated above, the SERM and parathyroid hormone may also have one or more additional drugs used as the first active ingredient in the treatment of osteoporosis.

Nitroglycerin (e.g., for the treatment of angina pectoris) provides an additional example of a second active ingredient in a dual drug delivery device according to the present invention. Oral (e.g., sublingual) administration of nitroglycerin is preferably combined with a time-controlled, immediate-release delivery system containing one or more additional angina drugs as the first active ingredient. The additional angina drug is preferably a beta-blocker such as, for example, atenolol, pindolol, propranolol, oxprenolol, metoprolol, and/or bisoprolol; calcium antagonists such as, for example, amlodipine, diltiazem, nifedipine, bepridil, barnidipine, nicardipine and verapamil; and/or a selective heart rate reducing component such as, for example, ivabradine.

In a most preferred embodiment, the second active ingredient is testosterone or a functional analogue thereof. This active ingredient is preferably used for treating men or women: sexual dysfunction, sexual desire dysfunction, erectile dysfunction, and preferably for the treatment of hypoactive sexual desire disorder. Preferably, the treatment is a combination therapy together with the first active ingredient, whereby testosterone or a functional analogue is provided in an immediate release formulation in the second coating and the first active ingredient is provided in the core of a time controlled, immediate release drug delivery system according to the invention.

The term "testosterone" or a functional analogue thereof refers to testosterone or a precursor or metabolite of testosterone that provides the same or similar function as testosterone. Preferred precursors of testosterone are selected from pregnenolone, 17 α -hydroxypregnenolone, progesterone, 17 α -hydroxyprogesterone, dehydroepiandrosterone, androstenedione, and androstenediol. Preferred metabolites of testosterone are selected from the group consisting of hydroxyandrostenedione, hydroxytestosterone (including 2 β -, 6 β -, 7 α -, 12 α -, and 16 α -hydroxytestosterones), and dihydrotestosterone (including 5 α -and 5 β -dihydrotestosterone). Preferred analogs of testosterone are capable of binding to the androgen receptor. Most preferably, the testosterone or functional analogue thereof is testosterone.

Said "testosterone or a functional analogue thereof" in the second coating is preferably combined with a PDE5 inhibitor, a NEP inhibitor, and/or a 5-HT1A receptor agonist. The dual drug delivery device comprising a time controlled, immediate release drug delivery system according to the present invention comprising a PDE5 inhibitor, a NEP inhibitor, and/or a 5-HT1A receptor agonist, wherein the first coating of the drug delivery system is surrounded by a second coating comprising testosterone or a functional analogue thereof, preferably provides a supply of the drug delivery system comprising a PDE5 inhibitor, a NEP inhibitor, and/or a 5-HT1A receptor agonist between 1.5-5 hours, more preferably 2-3 hours, more preferably about 2.5 hours of providing testosterone or a functional analogue thereof.

The second coating comprising a steroid such as testosterone or a functional analogue thereof preferably comprises a carrier selected from the group consisting of hydroxypropyl-beta-cyclodextrin, poly-beta-cyclodextrin, gamma-cyclodextrin and polyvinylpyrrolidone. The preferred polyvinylpyrrolidone is a low molecular weight polyvinylpyrrolidone having a maximum molecular weight of 80000. Suitable polyvinylpyrrolidones are preferably selected from K10, K15, K25, K30, and K50. The most preferred carrier is hydroxypropyl-beta-cyclodextrin. The presence of a poorly soluble steroid (such as testosterone) and a carrier (such as cyclodextrin) provides for rapid and efficient delivery of testosterone to the mucosa, through which the steroid is rapidly absorbed from the mucosa into the circulation. The amount of the carrier is preferably between 0.5% (w/w) and 70% (w/w), more preferably between 2% (w/w) and 60% (w/w), more preferably between 5% (w/w) and 50% (w/w), based on the total weight of the second coating.

The second coating preferably comprises a flavouring compound in addition to the second active ingredient and one or more excipients, such as a colouring agent. The flavouring compound may be any natural, artificial or synthetic compound or mixture of compounds that is pharmaceutically acceptable. An exemplary list of flavoring agents for pharmaceutical use includes cyclic alcohols, volatile oils, synthetic flavor oils, flavoring aromatics, oils, liquids, oleoresins, and extracts derived from plants, leaves, flowers, fruits, stems, roots, and combinations thereof. Non-limiting examples of cyclic alcohols include menthol, isomenthol, neomenthol, and neoisomenthol. Non-limiting examples of flavor oils include spearmint oil, cinnamon oil, oil of wintergreen (methyl salicylate), peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leaf oil, nutmeg oil, allspice, sage oil, nutmeg, bitter almond oil, cinnamon oil, and combinations thereof. Suitable flavorants also include, for example, artificial, natural, and synthetic fruit flavorants such as citrus oils (e.g., lemon, orange, lime, and grapefruit), fruit essences (e.g., lime, orange, lime, grapefruit, apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot, or other fruit flavorants). Other useful artificial, natural and synthetic flavorants include sugars, polyols such as sugar alcohols, artificial sweeteners such as aspartame, stevia, sucralose, neotame, acesulfame potassium, and saccharin, chocolate, coffee, vanilla, honey powder, and combinations thereof. Other useful flavorants include aldehydes and esters such as benzaldehyde (cherry, almond), citral (lemon, lime), neral (lemon, lime), decanal (orange, lemon), C-8 aldehyde (citrus fruit), C-9 aldehyde (citrus fruit), C-12 aldehyde (citrus fruit), tolylaldehyde (tolyl aldehyde) (cherry, almond), 2, 6-dimethyloctanal (green fruit), 2-dodecanal (tangerine), and combinations thereof. Preferred flavoring compounds are cyclic alcohols such as, for example, menthol, isomenthol, neomenthol and neoisomenthol, preferably in combination with artificial sweeteners such as aspartame. The amount of flavouring compound is preferably between 0.1% (w/w) and 60% (w/w), more preferably between 1% (w/w) and 40% (w/w), based on the total weight of the second coating.

The presence of the flavoring compound in the second coating of the dual drug delivery device according to the present invention may mask bitter or unpleasant tasting drugs or excipients.

Preferably, the flavouring compound in the second coating of the dual drug delivery device according to the invention disappears rapidly from the oral cavity. The perception of a particular flavour in the mouth indicates to the user that the second coating is not fully dissolved and that the time controlled, immediate release drug delivery system contained within the second coating is to be held in the mouth. During use, the second active ingredient is co-delivered with the fragrancing compound from the second coating. Due to the presence of the scent (taste), the subject can easily realize that the device is delivering the second active ingredient. Finally, the entire dose of the second active ingredient is delivered. At this point, the device also stops delivering scent. The disappearance of the aroma (taste) indicates that a time-controlled, immediate release drug delivery system can be ingested.

The skilled person will appreciate that the flavouring compound may be present in the first coating, rather than in the second coating. In that case, the appearance of the aroma (taste) indicates that a time-controlled, immediate release drug delivery system can be ingested. The skilled person will further understand that the first flavouring compound may be present in the second coating, while the second flavouring compound is present in the first coating. When the first scent (taste) disappears and the second scent (taste) is tasted, the subject knows that the device has delivered the full dose of the second active ingredient.

It is further preferred that in the device according to the invention the roughness of the outer surface of the second coating is different from the roughness of the outer surface of the first coating. When the difference in roughness becomes apparent, the subject may be instructed to swallow a time-controlled, immediate release drug delivery system. This provides a sufficient residence time of the device according to the invention in the mouth, such that the second active ingredient is sufficiently released and absorbed.

The invention further provides the use of a flavouring compound in a dual delivery pharmaceutical device to indicate that the device is to be held in the mouth until the flavour (taste) has disappeared.

The invention further provides the use of a flavouring compound in a dual delivery pharmaceutical device to indicate that the device is to be held in the mouth until flavour (taste) is present.

The present invention further provides a process for the preparation of a dual delivery drug device comprising a first coating and a second coating, wherein a flavoring compound is present in the second coating for indicating that the device is to be held in the mouth until the flavor (taste) has disappeared.

The present invention further provides a process for preparing a dual delivery drug device comprising a first coating and a second coating, wherein a flavoring compound is present in the first coating to indicate that the device is to be held in the mouth until flavor (taste) is present.

The present invention further provides the use of the difference in roughness between the first and second coating outer surfaces in a dual drug delivery device to indicate that the device is to be held in the mouth.

The present invention further provides the use of the difference in roughness between the first coating outer surface and the second coating outer surface in a dual drug delivery device to indicate that the device is about to be swallowed.

The present invention further provides a method for making a dual delivery drug device comprising a first coating and a second coating, wherein the roughness of the outer surface of the first coating is different from the roughness of the outer surface of the second coating.

In the present invention, it was found that the active ingredient present in the second coating of the drug delivery device as described herein above is well absorbed by the mucosa in the mouth. The absolute absorption and absorption rate as measured by bioavailability is significantly better when compared to a liquid with the same amount of active ingredient. Two variables were measured by measuring the concentration of the active ingredient in the blood of the subject at different time points after administration. Figure 11 depicts the results of a comparison of 0.5mg testosterone in liquid form (F1) with 0.5mg testosterone in a tablet of the invention (F2). The figure shows the concentration of total testosterone (a) and the concentration of free testosterone (B). The composition of the tablets is given in table 7. The composition of testosterone in liquid form is given in example 6. Both formulations were kept under the tongue of healthy volunteers for a period of 90 seconds. The absorption profile depicted is not expected. In the liquid phase, the active ingredient is already dissolved, whereas in tablets the active ingredient is present as a solid that needs to be dissolved before it can be used for absorption. This aspect is independent of the presence of the first coating on the core. The first coating may be present or absent.

Thus, the present invention further provides a tablet for sublingual administration of an active ingredient, said tablet comprising a core, and a coating on the outer surface of said core (outer coating) and optionally a coating separating said outer coating from said core (separating coating). In a preferred embodiment, the outer coating comprises testosterone or a functional analogue thereof. In a preferred embodiment, the core is a core for a time-controlled, immediate release drug delivery device as defined herein above. Preferably, the optional separate coating is a first coating for a drug delivery device as herein above identified, and preferably the outer coating is a second coating for a dual drug delivery device as herein above defined. In particular, it is preferableAn embodiment of (a), said outer coating comprises a mixture of active ingredients present in amorphous form in an amount between about 0.1mg to 10 mg; a coating polymer in an amount between about 0.25mg to 25 mg; and water in an amount between about 0.0% w/w to 10% w/w of the outer coating. The active ingredient in amorphous form is preferably the second active ingredient for dual drug delivery devices as indicated herein above. In a preferred embodiment, the active ingredient in amorphous form is testosterone or a functional analogue thereof. The functional analogue of testosterone is preferably a functional testosterone analogue as defined herein above. In a particularly preferred embodiment, the active ingredient is testosterone. In this embodiment, the mixture preferably further comprises cyclodextrin or polyvinylpyrrolidone or a combination thereof in an amount between 0.25mg and 25 mg. In a preferred embodiment, the mixture comprises the active ingredient in an amount between about 0.2mg to 5.0 mg; said coating polymer in an amount between about 0.5mg-12.5 mg; and water in an amount between about 0.0% w/w to 5% w/w of the outer coating. In this embodiment, the mixture preferably further comprises cyclodextrin or polyvinylpyrrolidone or a combination thereof in an amount between 0.25mg and 25 mg. However, the mixture may comprise cyclodextrin or polyvinylpyrrolidone or a combination thereof, preferably the mixture comprises cyclodextrin. Tablets with a mixture comprising cyclodextrin and not comprising polyvinylpyrrolidone are more stable, especially when the active ingredient is testosterone or a functional analogue thereof. Both the cyclodextrin and the polyvinylpyrrolidone prevent the crystallization of amorphous testosterone or a functional analogue thereof in the solid coating upon exposure to prolonged holding and/or various temperatures, as may occur during storage of the tablet. The coating polymer used for the outer coating is preferably the film forming component of the second coating indicated herein above for a dual drug delivery device. The mixture preferably further comprises a sweetener and/or a flavour as defined herein above. In a preferred embodiment, the outer coating consists of the mixture. As noted herein above, the tablet of this embodiment may comprise a separate coating separating the outer coating from the coreAnd (5) clothes. When present, the release coating is preferably a pH independent coating or a pH dependent coating, preferably an acid soluble coating or an enteric coating. In another preferred embodiment, the release coating is a first coating for a drug delivery device as defined herein above. The release coating preferably comprises a hydrophobic polymer and a hydrophilic substance as defined herein above for use in a drug delivery device. In this preferred embodiment, the core and the optional release coating have a thickness of between 50mm³-1000mm³The volume in between. Preferably, the core comprises cellulose for a drug delivery device as defined herein above, a filler (such as an organic salt and/or an inorganic salt) for a drug delivery device as defined herein above and an active ingredient. Preferably, the active ingredient is the first active ingredient for a drug delivery device as defined herein above.

The present invention further provides a method for administering an active ingredient to an individual, the method comprising providing an individual in need thereof with a dual drug delivery device or tablet according to the present invention, wherein the individual holds the dual drug delivery device or tablet in the mouth for 10 seconds to 5 minutes, and wherein the individual subsequently swallows the dual drug delivery device or tablet. In a preferred embodiment, the individual holds the dual drug delivery device or tablet in the mouth for 30 seconds to 2.5 minutes before ingesting the dual drug delivery device or tablet. Preferably, the individual holds the dual drug delivery device or tablet in the mouth for 60 seconds to 90 seconds before ingesting the dual drug delivery device or tablet. In a preferred embodiment, the dual drug delivery device or tablet is maintained under the tongue for a specified time. In a particularly preferred embodiment, the dual drug delivery device or tablet is placed under the tongue, where the individual gently holds or moves (e.g., swish) the dual drug delivery device or tablet for about 90 seconds. Preferably, the individual does not ingest the dual drug delivery device or the tablet or saliva during retention in the mouth and preferably under the tongue. The individual preferably does not chew or bite on the dual drug delivery device or tablet. When the holding time is over, the individual preferably ingests the dual drug delivery device or tablet as a whole, optionally together with a fluid such as water.

A dual drug delivery device or tablet comprising testosterone or a functional analogue thereof (or as a second active ingredient) in the outer coating may advantageously be used for the treatment of males or females: sexual dysfunction, sexual desire dysfunction, erectile dysfunction, and preferably for the treatment of hypoactive sexual desire disorder. Thus, the present invention further provides a dual drug delivery device or tablet of the invention for sublingual administration of testosterone or a functional analogue thereof for the treatment of male or female: sexual dysfunction, sexual desire dysfunction, erectile dysfunction, and preferably for the treatment of hypoactive sexual desire disorder, wherein the dual drug delivery device or tablet comprises a core, and a coating on the outer surface of the core (outer coating) and optionally a coating separating the outer coating from the core (separate coating), wherein the outer coating comprises the testosterone or functional analogue thereof.

In a further preferred embodiment, a dual drug delivery device or tablet comprising testosterone or a functional analogue thereof (or as a second active ingredient) in the outer coating may advantageously be used for the treatment of male hypogonadism. Thus, the present invention further provides a dual drug delivery device or tablet of the present invention for sublingual administration of testosterone or a functional analogue thereof for the treatment of male hypogonadism, wherein said dual drug delivery device or tablet comprises a core, and a coating on the outer surface of said core (outer coating) and optionally a coating separating said outer coating from said core (separate coating), wherein said outer coating comprises said testosterone or a functional analogue thereof.

In a further preferred embodiment, a dual drug delivery device or tablet comprising an estrogen and/or a progestin or their functional analogs (or as second active ingredients) in the outer coating can be advantageously used for the treatment of female hypogonadism. Thus, the present invention further provides a dual drug delivery device or tablet of the invention for sublingual administration of an estrogen and/or a progestin or functional analogue thereof for the treatment of hypogonadism in women, wherein said dual drug delivery device or tablet comprises a core and a coating on the outer surface of said core (overcoat) and optionally a coating separating the overcoat from said core (separation coating), wherein said overcoat comprises said estrogen and/or progestin or functional analogue thereof.

A preferred dual drug delivery device according to the present invention comprises:

and (3) nucleus:

pharmacel pH102 between 100mg and 150mg, preferably between 109mg and 126.5 mg;

calcium hydrogen phosphate 0aq between 100mg and 150mg, preferably between 109mg and 126.5 mg;

sildenafil citrate between 25mg and 100mg, preferably between 35mg and 70 mg;

between 10mg to 20mg, preferably about 12mg of crosslinked carboxymethylcellulose;

between 1mg and 2mg, preferably about 1.5mg, of magnesium stearate;

first coating:

between 5mg and 20mg, preferably about 12.5mg of ethylcellulose 20;

avicel pH105 between 5mg to 20mg, preferably about 12.5 mg;

and (3) second coating:

between 1mg to 2mg, preferably about 1.34mg, HPMC 5 cps;

between 2mg and 3.5mg, preferably about 2.66mg, of hydroxypropyl B-cyclodextrin;

between 0.1mg and 1mg, preferably between 0.25mg and 0.5mg of testosterone.

The second coating of the preferred dual drug delivery preferably further comprises between 1mg to 2mg, preferably about 1.34mg of peppermint oil and between 0.5mg to 1.5mg, preferably about 1.0mg of aspartame.

A further preferred dual drug delivery device according to the present invention comprises:

and (3) nucleus:

pharmacel pH200 between 50mg to 150mg, preferably between 75mg to 125mg, preferably about 97.5 mg;

0aq between 150mg and 250mg, preferably between 175mg and 225mg, preferably about 201.5mg of dibasic calcium phosphate;

buspirone hydrochloride in an amount between 1mg and 20mg, preferably between 5mg and 15mg, preferably about 10 mg;

between 10mg and 20mg, preferably about 13mg of crosslinked carboxymethylcellulose;

between 1mg and 10mg, preferably between 2mg and 5mg, preferably about 4.4mg magnesium stearate;

first coating:

between 5mg and 20mg, preferably about 14.7mg of ethylcellulose 20;

avicel pH105 between 10mg to 50mg, preferably between 20mg to 40mg, preferably about 29.3 mg;

and (3) second coating:

between 1mg to 2mg, preferably about 1.34mg, HPMC 5 cps;

between 0.1mg and 1mg, preferably between 0.25mg and 0.5mg of testosterone.

Drawings

FIG. 1 in vitro release profile of ethylcellulose coating. This figure shows the release profile of one tablet coated with a mixture of ethylcellulose 45 and lactose 200 mesh (11 a). The rupture at a lag time of 1.90h 12min is equal to the rupture of the other coatings described in tables 1-3. Over 80% of the drug was released within 6 minutes.

FIG. 2 is a Scanning Electron Microscope (SEM) micrograph showing coating surface features. Black dots are holes on the surface.

(A) Tablets coated with ethylcellulose/Avicel PH105(1: 1). A plurality of pores are present before rupturing and (B) after rupturing.

(C) The ethylcellulose/lactose 450m (1:1) coating contains hardly any pores.

(D) When the coating is ruptured, a plurality of pores are formed.

Fig. 3 SEM micrograph showing a cross section of the first coating before the coating ruptures. (A) ethylcellulose/Avicel (1: 1). (B) Ethylcellulose/lactose 450 m.

Figure 4 coating break time versus average coating weight of sildenafil core tablets as obtained on a porous drum film coater. The data are for a first coating with 60% Avicel and 40% ethylcellulose (coating weight range 25mg to 32 mg) and a first coating with 67% Avicel and 33% ethylcellulose (coating weight range 34mg to 46 mg). Black lines: a maximum value. Deep gray line: average value. Shallow gray line: a minimum value.

Fig. 5. testosterone was measured against the weight of a second coating solution comprising testosterone. The second coating solution was sprayed in a porous drum film coater, indicating that the spray weight is the appropriate endpoint for the coating process to obtain the appropriate content uniformity for testosterone.

FIG. 6 geometric mean of total testosterone levels in serum after sublingual administration of 0.25mg, 0.50mg and 0.75mg testosterone.

Total testosterone normally ranges from 0.14ng/mL to 0.66ng/mL (0.5nmol/L to 2.3nmol/L) (Davison et al, 2005). To convert total testosterone to nanomoles/liter, 3.467 was multiplied.

FIG. 7 geometric mean of free testosterone levels in serum after sublingual administration of 0.25mg, 0.50mg and 0.75mg testosterone.

The normal range for free testosterone is 0.00072 to 0.0036ng/mL (2.5 to 12.5pmol/L) (Davison et al, 2005). To convert free testosterone to picomoles/liter, 3467 was multiplied.

Figure 8 free fractions of testosterone measured from t 4min to t 30min for 0.25mg, 0.50mg and 0.75 mg.

Figure 9 free fractions of testosterone for 0.25mg, 0.50mg and 0.75mg measured from t-4 min to t-30 min for the high and low SHBG groups.

Significant difference between 0.25mg and 0.75mg (P ═ 0.05)

Significant difference between 0.25mg and 0.50mg (P ═<0.05)

FIG. 10 geometric mean values of DHT levels in serum after sublingual administration of 0.25mg, 0.50mg and 0.75mg of testosterone. DHT reference range <0.29ng/mL (Davison et al, 2005). To convert the total DHT to nanomole/liter, multiply by 3.44.

Figure 11 comparison of testosterone bioavailability measured by uptake in the blood of healthy individuals following administration of testosterone in a liquid formulation (F1) or the same amount (0.5mg) of testosterone in a solid formulation (F2).

Figure 12 mean testosterone plasma concentration-time profiles measured in healthy pre-menopausal female subjects.

Figure 13 mean free testosterone plasma concentration versus time profiles measured in healthy pre-menopausal female subjects.

Figure 14 mean plasma concentration versus time profiles of sildenafil measured in healthy premenopausal female subjects.

FIG. 15 is a graph of the in vitro release of a single sildenafil core coated with 21.5mg of ethylcellulose/Avicel PH105(1: 1).

FIG. 16 is a graph of the in vitro release of sildenafil coated with 21.5mg of ethylcellulose/Avicel PH105(1: 1).

Detailed Description

Examples

Materials and methods

Chemical products

Magnesium stearate; theophylline; crosslinked carboxymethylcellulose (AC-DI-

) (ii) a And ethyl cellulose (ethyl cellulose 20, 45 (Standard premium)) is available from dow (benelux). Microcrystalline cellulose (Avicel PH101, PH102, and PH105) and sodium carboxymethylcellulose (low viscosity) were obtained from OPG Farma. Corn starch (Maydis Amyllum) was obtained from OPG Farma. Lactose 200 mesh and 450 mesh (Pharmatose) were obtained from DMV-Fonterra.

Preparation of the core

A core tablet containing the drug was prepared by mixing 50mg theophylline, 12mg Ac-Di-Sol, 119mg microcrystalline cellulose (Avicel PH102), and 119mg calcium phosphate. The core tablet excipients were blended in a Turbula-mixer for 15min, then magnesium stearate (0.5% w/w) was added. The powder mixture was further mixed for 2 min. The core tablets (diameter, 9 mm; biconvex; hardness, 100N; average tablet weight, 300mg) were compressed at 10 kN.

Preparation of the coating

Film coating was performed in the lower half of the flat bottom flask at 45 rpm. The flask was heated by hot air to ensure evaporation of the solvent. The core tablets were heated for 45 minutes for dehydration prior to the coating process. The solution of ethanol and ethyl cellulose (3%) was continuously stirred with the particles in suspension to ensure a homogeneous suspension. The suspension was sprayed onto the tablets at a rate of-1 ml/min. The weight gain of the tablets was determined by weighing the tablets periodically during the coating process.

In vitro dissolution test

To determine how much drug was released from the formulation over time, dissolution experiments were performed using USP dissolution apparatus No. II (Prolabo, Rowa techniek BV) using a rotational speed of 100 rpm and 500ml of medium at 37 ℃ (n ═ 5). The dissolution medium used comprised 0.1M phosphate buffer at pH 6.8. The amount of dissolved theophylline was determined by UV absorbance at a wavelength of 269 nm. The lag time is defined as the intersection on the time axis when 25% of the drug in the tablet is released. Figure 1 illustrates the burst pattern found for all coatings. After the lag time, more than 80% of the drug is released within 6 minutes.

Scanning electron microscope

Scanning electron micrographs of cross sections of the coating film of the pulse release tablets were taken using a scanning electron microscope (JEOL 6301F) before and after dissolution test in pH 6.8 phosphate buffer.

Example 1 coating of ethylcellulose and Avicel

The theophylline containing cores were coated with ethylcellulose 20 (3%) and various grades of Avicel (microcrystalline cellulose) to establish a time controlled immediate release of theophylline after about 2 hours. Avicel is widely used in many pharmaceutical formulations. Avicel PH-105, PH-101, and PH-102 were tested because they were chemically identical, but they exhibited a range of particle sizes (nominal particle sizes of 20 microns, 50 microns, and 100 microns, respectively).

TABLE 1 in vitro lag time of tablets coated with ethylcellulose and Avicel.

The drug release lag time and corresponding coating formulation are provided in table 1.

The lag time depends on a variety of variables. One of these variables is the particle size. As shown in table 1, Avicel 105 particles having a nominal particle size of 20 microns delayed the cracking of the coating compared to Avicel 102 particles and Avicel 101 particles (compare composition 3b to compositions 2 and 8). This effect can be explained by the increased time required for 20 micron particles to penetrate water due to increased hydrophobic interactions. This results in less capillary action and therefore less water is absorbed in time. This results in a lower rate of water transport into the inner core and an increased lag time. The small particle size of microcrystalline cellulose also causes a large variation in the results.

The lag time also depends on the thickness of the coating as determined by the weight of the tablet (compare composition 3b with composition 3a of table 1). A thinner coating may allow the fluid to more easily penetrate into the core, resulting in a shorter lag time for disintegration. In addition, thinner coatings are less hard and disintegrate more easily, which also reduces lag time.

An additional parameter that affects the lag time is the ethylcellulose 20/Avicel ratio. The ratio of 1:1 instead of 3:2 (compare compositions (3b) and (4b) in table 1) results in increased transport of water due to the larger amount of particles transporting water to the core. This results in a reduction in the lag time and the observed variation in the results. The coating with 100 micron Avicel particles (2) and the coating with 20 micron particles (4b) have approximately the same weight and lag time, but different ratios of ethylcellulose/Avicel. Thus, changing the ratio of ethylcellulose/Avicel from 3:2 to 1:1 offsets the increase in lag time by using smaller Avicel particles. The advantage of using smaller particles is that the coating suspension has better flow properties, which improves the overall film coating process.

The surface of the ethylcellulose/Avicel coating was examined by Scanning Electron Microscopy (SEM). A number of pores (a and B in fig. 2) were found before and after the rupture. These directly connect the core to the outside through the pore passages of the coating, as shown in the cross-section of the coating (a in fig. 3). These holes enable water to be transported directly into the nucleus, possibly after or instead of being transported via Avicel pellets.

Example 2 coating of ethylcellulose and lactose

A further structure for establishing a pH independent, time controlled influx of water into the core comprises a first coating having hydrophilic, water soluble microparticles within a hydrophobic layer. After a certain lag time, the soluble component will dissolve, leaving pores that can transport water into the core. This results in disintegration of the core, rupture of the coating and release of the first active ingredient from the drug delivery system. Thus, in addition to the diffusion rate of the medium through the pores, the medium influx is also dependent on the dissolution rate of lactose.

Lactose was chosen because there is a wide range of available particle sizes that can be used as a formulation variable. Lactose is a disaccharide comprising galactose and glucose. Table 2 shows the different formulations and the corresponding lag times.

Table 2 in vitro lag time of tablets coated with ethylcellulose and lactose.

When the 450 mesh ratio of ethylcellulose/lactose was changed from 3:2 to 1:1, the total number of pores connecting the outside of the coating to the core would increase. A coating with a 1:1 ratio (ethylcellulose/lactose) will allow faster diffusion of the medium to the core compared to 3:2, which will result in earlier breaking of the coating and thus reduced lag time. This would be coated by (8b)13mg in table 2; lag time of 85min (3:2) and (9a), 15mg coating; a lag time of 47min (1:1) is shown. The increase in the amount of lactose in the coating resulted in little variation between tablets (compare formulation (9) and formulation (8)).

All ethylcellulose coatings containing lactose reach the weight limit where the coating does not break, e.g., 8c, 9c, 10c, and 11 b. When the coating is thicker, the chances of forming pores connecting the outside of the coating with the core become smaller. If the coating becomes too thick, there is too little chance of forming a hole connecting the outside of the tablet with the core. Thus, transport of water to the core will not occur, maintaining the tablet intact.

SEM micrographs of ethylcellulose/lactose coated tablets show that the intact coating contains hardly any pores (C in fig. 2), while the ruptured coating shows the formation of many pores (D in fig. 2). Furthermore, unlike the ethylcellulose/Avicel coating (B and a in fig. 3, respectively), the cross-section of the coating (B in fig. 3) shows that the intact ethylcellulose/lactose coating contains hardly any pores.

EXAMPLE 3 preparation of the preferred drug delivery System

Preparation of the core

Material

Croscarmellose, ViVaSol, JRS Pharma, Ph. Eur., batch (batch)9907

Anhydrous calcium hydrogen phosphate, Budenheim, USP.

Magnesium stearate, Bufa, ph. eur, lot (lot)04j22fs

-Pharmacel PH102，DMV-Fonterra，Veghel

Sildenafil citrate

All materials except magnesium stearate were mixed for 15 minutes at 90 rpm using a Turbula mixer. After the addition of magnesium stearate, the mixture was further mixed for 2 minutes.

Tablets were prepared using an instrumented eccentric press (HOKO) with a 9mm biconcave die set. The pressure was 10 kN. The tablet weight was about 300 mg.

TABLE 3 composition of the core:

coating of cores

Material

-ethyl cellulose 20, Dow Benelux, batch number KI 19013T02

Avicel PH105, FMC, Ph. Eur, batch No. 50750C

Preparation of the first coating solution

A 50ml solution containing 3% ethylcellulose (═ 1.5g ethylcellulose) was prepared in 96% ethanol. 1.5g Avicel PH105 was added to the suspension.

The first coating solution was sprayed onto a batch of tablets in a small spray container (glass) using a spray nozzle (0.7mm inner diameter). The suspension was stirred during the entire process. During this process, the spray vessel was heated with hot air to evaporate the solvent. The coating process was stopped when approximately 25mg of ethylcellulose/Avicel was sprayed onto each tablet.

EXAMPLE 4 preparation of a preferred Dual drug delivery device

Material

Testosterone, Sigma

HPMC 5cps, Ph. Eur, Sigma-Aldrich, batch No. 12816TD

-hydroxypropyl-beta-cyclodextrin m.s. ═ 0.8, Aldrich, ph.eur, batch No. 30638-

Peppermint oil, Bufa, Ph. Eur, Lot 09j16-B01

Aspartame, Bufa, ph. eur, lot No. 02a17fr

Preparation of the solution

5% HPMC solution: 5g HPMC 5cps was dissolved in 85ml 96% ethanol +15ml demineralized water (demi-water).

5% HPBCD solution: 5g HPBCD was dissolved in 100ml 96% ethanol.

1% peppermint oil: dissolving 1g oleum Menthae Dementholatum in 100ml 96% ethanol

Second coating solution

6.7ml 5% HPMC solution 0.335g HPMC 5cps

13.3ml of 5% HPBcd solution ═ 0.665g hydroxypropyl B-cyclodextrin

30ml of 1% peppermint oil solution 0.3g of peppermint oil

0.250g aspartame-0.250 g aspartame

0.125g testosterone to 0.125g testosterone

20ml of demineralized water

Total volume: 70ml of

The second coating solution was sprayed onto a batch of tablets comprising a core and a first coating as shown in example 3 using a nozzle (0.7mm inner diameter). Spraying was carried out in a small spray container (glass). The container was heated with hot air to evaporate the ethanol. The coating process was stopped until injection of 0.5mg testosterone/tablet (6.7mg total weight).

TABLE 4. composition of the second coating of the dual drug delivery device

TABLE 5 preferred dual drug delivery devices

TABLE 6 preferred Dual drug delivery device

EXAMPLE 5 preparation of a preferred Dual drug delivery device

Sildenafil citrate, anhydrous dibasic calcium phosphate, microcrystalline cellulose and croscarmellose are combined and mixed in a container. The mixture was passed through a 600 micron mesh into a blending vessel. The blend was allowed to tumble for 30 minutes. Magnesium stearate was passed through a 600 micron mesh and added to the blend. The blend was lubricated by tumbling for up to 10 minutes. The blend was then placed in a tablet press equipped with 9mm biconcave punches and compressed into 300mg tablets by weight. Ethylcellulose and microcrystalline cellulose were dispersed in ethanol, and the uncoated tablet cores were loaded into a porous drum membrane coater. The dispersed ethyl cellulose and microcrystalline cellulose were sprayed onto the core, and the solvent was removed by heating. The tablets are allowed to cool gradually in the coating machine before the next coating step.

Hydroxypropyl β -cyclodextrin was dispersed in water. Testosterone was dissolved in ethanol. After the addition of the organic and aqueous phases, stirring was performed to allow testosterone to interact with the cyclodextrin. Aspartame, menthol and hydroxypropyl methylcellulose (hypromellose) were added and stirring was continued. The resulting suspension was sprayed onto the coated core tablets described above in a perforated drum coating pan. The solvent was removed by heating with air.

According to this process, tablets having various coating break times were manufactured by modifying the first coating composition and the first coating weight as shown in fig. 4. To this end, the cores were coated with 60% Avicel and 40% ethylcellulose by weight 25.7mg, 29.0mg and 31.2mg, or with 67% Avicel and 33% ethylcellulose by weight 34.3mg, 40.9mg and 45.3 mg.

Figure 5 shows that the weight of the sprayed second coating solution is an excellent indicator for the total amount of testosterone applied to the tablet in order to determine the end point of the coating process with testosterone coating. The testosterone content uniformity of the three batches as described in figure 5 is well within the pharmacopoeia requirements with relative standard deviations of 4.2%, 2.8% and 3.1% for batches MOR202/66, MOR202//71, and MOR202//75, respectively.

Example 6

Background: sublingual testosterone is a single dose treatment often used in studies on social, cognitive and sexual behavior. It is hypothesized that an increase in the ratio of free testosterone to total testosterone (free fraction) is indirectly responsible for the behavioural effects following sublingual testosterone administration by genetic action.

The target is as follows: the pharmacokinetics of sublingual testosterone were characterized in premenopausal women at three doses. In addition, SHBG saturation thresholds were studied that affect the free level and free fraction of testosterone.

Designing: we performed blinded, randomized, cross-placebo controlled studies of investigators.

Setting: this study was conducted in the research and development department of science and technology companies directed to research related to female sexual dysfunction.

The participants: 16 healthy premenopausal women (mean age 27.3 ± 5.3 years).

The measures are as follows: a sublingual testosterone solution; 0.25mg, 0.50mg and 0.75 mg.

Measurement of main results: pharmacokinetics of three single dose sublingual testosterone solutions; effect of SHBG levels on free and total levels of testosterone.

As a result: following sublingual testosterone administration, serum free testosterone levels and total testosterone levels peak at 15 minutes and reach baseline levels within 150 minutes. AUC and C for free and total testosterone between three doses_{Maximum of}Is obviously different from (P)<0.0001), and increases dose-dependently.

A dose-dependent increase in testosterone free fraction was found in women with low SHBG levels, but not in women with high SHBG levels.

And (4) conclusion: in premenopausal women, three doses of sublingual testosterone are rapidly absorbed and metabolized rapidly. These data indicate that the effect of SHBG levels on treatment causes a change in plasma free testosterone.

Introduction to

Results of scientific studies indicate that testosterone is associated with social behaviors (Bos et al, 2010; Eisenegger et al, 2010), including sexual behaviors (Auger, 2004; Hull and dominguz, 2007). Sexual behavior is affected by endogenous testosterone levels as well as exogenously administered testosterone. For exogenous testosterone administration, two different treatment methods can be distinguished: chronic treatment and single dose administration. Each treatment has its own pharmacokinetic profile, which can affect the effect of testosterone on behavior. In most studies related to the effect of testosterone on female sexual behavior, including hormone replacement therapy in natural or surgical (bilateral ovariectomy) menopausal women, chronic testosterone administration was used as the delivery option (Sherwin, 2002; Shifren et al, 2000; Simon et al, 2005).

However, recently, several studies have investigated the effect of a single dose of testosterone administration on female sexual behavior (Tuiten et al, 2000; Tuiten et al, 2002; van der Made et al, 2009). Tuiten et al reported that a single sublingual dose of 0.50mg testosterone significantly improved the experience of vaginal vascular congestion and sexual desire and genital sensation in premenopausal women without sexual disorder (Tuiten et al, 2000). These effects occurred 3h to 41/2h after the peak induced testosterone and about 21/2h after testosterone returned to baseline levels. This delay in behavioral effects after sublingual testosterone administration has been repeated in several other studies related to social behavior and cognitive function (Aleman et al, 2004; Bos et al, 2010; Eisenegger et al, 2010; Hermans et al, 2006; Hermans et al, 2007; Hermans et al, 2008; Postma et al, 2000; Schutter and van Honk, 2004; van Honk et al, 2001; van Honk et al, 2004; van Honk et al, 2005; van Honk and Schutter, 2007).

Few studies have defined the pharmacokinetic profile of sublingual testosterone. Salehian et al (Salehian et al, 1995) compared the pharmacokinetic profile of two doses of sublingual testosterone (2.5mg and 5.0mg) with the pharmacokinetic profile of the long-acting testosterone ester, Testosterone Enanthate (TE) (in oil, im.200mg) in hypogonadal men. Total and free testosterone levels peaked after several days in the studied male subjects receiving TE compared to sublingual testosterone. In sublingual conditions, an increase in free testosterone levels occurs within 1h after administration, in the TE group, which occurs 7 days after administration. Furthermore, it was shown that free testosterone levels in TE conditions did not increase until Sex Hormone Binding Globulin (SHBG) levels were inhibited at day 7 post-dose. The inhibition of SHBG levels was significantly greater in the TE group than in the sublingual group (Salehian et al, 1995).

It is widely accepted that free testosterone is biologically active testosterone (Mendel, 1989). The pharmacodynamic effect (measurement of sexual function) would therefore be expected to increase later in the TE dosed group compared to the sublingual dosed group. However, in the Salehian et al study, sexual motivation after dosing was measured first one week prior to the first visit on day 20, when free testosterone elevation had ceased in both groups. Notably, in the study by Tuiten and Van der Made et al, the measure of sexual arousal increased 31/2 to 4h after peak circulating testosterone (Tuiten et al, 2000; Van der Made et al, 2009) and 2.5 hours after testosterone levels returned to baseline, indicating that sublingual testosterone administration produced a pharmacodynamic effect after 4 hours. The SHBG saturation threshold hypothesis is proposed by Van der Made et al; i.e. when the effective binding site of SHBG is occupied by testosterone after a sufficient single sublingual dose of testosterone, the free fraction and free testosterone levels are therefore increased, causing a behavioral effect (van der Made et al, 2009). The exact mechanism responsible for this delay in behavioral effects is not fully understood, but it is likely that testosterone exerts its behavioral effects through androgen metabolites, genomic mechanisms (Bos et al, 2011), or a combination of these factors.

The main objective of this study was to establish a broad pharmacokinetic profile of sublingual testosterone as three different single doses administered as solutions with cyclodextrins. The primary pharmacokinetic endpoints are the levels of total testosterone and free testosterone. The secondary endpoints include the pharmacokinetics of 5 α -Dihydrotestosterone (DHT), and 3 α -androstanediol glucuronide (3 α -diol-G). Serum albumin, 17 beta-estradiol (E) was also measured₂) And SHBG.

Furthermore, we compared the data from this study with that from the pharmacokinetic study of Tuiten et al (Tuiten et al, 2000) with respect to the effect of a single dose of sublingual testosterone on circulating free and total testosterone levels. Furthermore, we tried to determine at what level serum testosterone occupied the effective binding site of SHBG and increased serum free testosterone, i.e. the SHBG saturation threshold mechanism assumed by van der Made et al (van der Made et al, 2009).

Subject and method

Study Subjects

Eligible women are between 21 and 40 years of age, pre-menopausal, and have a weight of 18kg/m²To 30kg/m²Human Body Mass Index (BMI) in between. Exclusion criteria included history of hormone-dependent malignancies, endocrine diseases, neurological problems, psychiatric abnormalities, cardiovascular disease, hypertension, liver or kidney dysfunction. Women treated with drugs that interfere with sex steroid metabolism or with testosterone within 6 months prior to study entry were also excluded.

Women were recruited and enrolled by recommenders, newspaper ads, the internet, and our laboratory's internal databases. To qualify, participants were screened two weeks prior to study entry. All subjects received physical examination, including 12-lead electrocardiography, standard biochemical and hematological laboratory tests, except for an assessment of medical history. Blood samples for the determination of testosterone, SHBG, TSH, thyroxine, FSH and estrogen were collected at baseline. Urine pregnancy tests were performed on all women carrying the possibility of children.

16 healthy young women participated in the study after providing written informed consent and receiving compensation for their cost of participation. This study was approved by The local ethical committee (Stichting therapeutic university medical science, Almere, The Netherlands) and was conducted in compliance with ICH-GCP (International Conference on standardization-Good Clinical Practice).

Design of research

This is a single-center, investigator-blind, randomized, cross-placebo controlled study that utilizes three doses of testosterone solution containing cyclodextrin administered sublingually. The solution consists of true non-modified testosterone that forms a soluble complex through a cyclodextrin carbohydrate ring. Due to the increased solubility, absorption of testosterone via the oral mucosa is promoted, thereby avoiding hepatic first-pass metabolism (Brewster et al, 1988; Salehian et al, 1995; Stuenkel et al, 1991; Zhang et al, 2002).

All 16 subjects received one dose of each study drug in random order. Washout between treatments was at least 48 hours. The subject has a series of blood samples drawn via an intravenous catheter. Pharmacokinetic parameters were monitored at baseline and after dosing (at 2,4, 6, 8, 10, 20, 30, 60, 90, 120, 180, 230 minutes).

Measurements of total testosterone, free testosterone, and DHT were taken at each sampling time; e at-5, 60, and 230min₂Measuring (2); measurements of 3 α -diol-G were taken at-5, 60, 120, and 230 minutes; SHBG and albumin measurements were performed prior to dosing and at 230 minutes. Blood samples in placebo conditions were measured only at-5, 10, 60 and 230 minutes.

Vital signs were measured at regular intervals and electrocardiograms were taken before dosing and at the end of the experimental day. For each experimental day, subjects were asked to participate in the visit in a fasted state, and they received a strict diet during the experimental day to minimize the impact of pharmacokinetic parameters. Drug, ethanol and pregnancy screens were performed prior to the experimental period.

Drugs and dosages

Testosterone and placebo were administered sublingually in 4 separate experimental sessions using 0.25mg, 0.50mg, 0.75mg doses and placebo as solutions taken from 1mg/ml solution using a micropipette (Gilson Pipetman P1000). 0.25mg, 0.50mg and 0.75mg testosterone from different volumes of 1mg/ml solution were administered. For placebo solution, 0.50ml was administered.

Different doses were prepared and administered by blinding (unlined) study assistants. The blind study assistant dosed the solution into the mouth of the subject under the tongue, instructing the subject to hold the solution under the tongue for 1 minute while gently moving the tongue to optimize absorption. After 1 minute, the blind study assistant instructed the subject to swallow the solution.

Hormone assay

The assays used to determine total testosterone, free testosterone (after ultrafiltration), and DHT were high performance liquid chromatography and mass spectrometry detection (LC/MSMS) (API 4000, AB Sciex). The method was validated using a lower limit of quantitation (LLOQ) of 0.02ng/mL for testosterone and DHT and 0.001ng/mL for free testosterone. The LC/MSMS assay is a reliable method for the analysis of free testosterone and overcomes the known limitations of direct immunoassays in the measurement of testosterone values in the lower range (Labrie et al, 2006; Miller et al, 2004).

Analysis of E by chemiluminescence immunoassay (Siemens)₂LLOQ was 0.25 pmol/L. 3 α -diol-G was measured by ELISA (BioVendor) and LLOQ was 0.25 ng/mL. SHBG was measured by electrochemiluminescence assay (ECLIA, roche). Albumin was measured by Roche bromocresol green (BCG) assay (Roche).

Statistical analysis

Pharmacokinetic parameters were analyzed using WinNonlin software (version 5.1). Based on the actual and baseline corrected individual concentration time curves, pharmacokinetic parameters were calculated, including the area under the curve from t 0min until t 230min (AUC)_0-230) Maximum concentration (C)_{Maximum of}) And the time (t) to reach maximum concentration_{Maximum of}). AUC was estimated using the linear trapezoidal rule. AUC for individual pharmacokinetic parameters_0-230And C_{Maximum of}And the corresponding dose normalization parameters were log transformed and analyzed using a MIXED maximum likelihood analysis (PROC MIXED in SAS, version 9.1), including subjects as random factors and drugs as fixed-action factors. Least squares comparisons were made to compare different doses. T was analyzed using Wilcoxon rank sum test (Wilcoxon rank sum test)_{Maximum of}. This is based on the comparison with the actual t_{Maximum of}The time is scheduled accordingly to prevent bias in the analysis results based on the sampling time difference.

Total and free testosterone, DHT, E were calculated by averaging placebo, 0.25mg, 0.50mg, 0.75mg pre-dose levels ₂3 alpha-diols-G, SHBG and baseline levels of albumin.

Bulk analysis of free fraction (free testosterone levels at each time point divided by total testosterone levels) was analyzed using drug and time as within the subject factors, measured in 3 drugs (0.25mg versus 0.50mg versus 0.75mg) x 6 times (

t

4, 6, 8, 10, 20, 30min) repeatedly.

To satisfy the normal assumption, baseline SHBG values were logarithmically transformed and Pearson's correlation coefficient (Pearson's correlation coefficient) was calculated to further study the relationship between SHBG levels, total testosterone, free testosterone, and free percent testosterone.

Subsequently, we divided the subjects into two sub-groups based on their baseline SHBG levels (placebo, 0.25mg, 0.50mg, average of 0.75mg pre-dose levels). This subdivision is based on median split (median split) of the baseline SHBG level. One group (N ═ 8) had low SHBG levels (≦ 63nmol/L), while the other group (N ═ 8) had relatively high SHBG levels (>63 nmol/L). For measurements after each dose, t-tests of independent samples were used to assess free testosterone levels and SHBG as grouping variables (low SHBG versus high SHBG).

Dependent variable free fraction was analyzed using drug and time as within subject factors and group as between subject factors, repeated measurements at 3 drugs (0.25mg and 0.50mg and 0.75mg) x 6 times (t ═ 4, 6, 8, 10, 20, 30min) x 2 groups (low SHBG and high SHBG). To analyze the effect within the subject factors within each group individually, a paired sample t-test was used for each SHBG group for each post-dose measurement between the three doses. For all ANOVA, there was no sphericity violation. For all analyses, p-values (double-sided) of less than 0.05 were considered statistically significant. SPSS 16.0 was used for all statistical analyses.

Results

Baseline characteristics and hormone levels for 16 study participants are summarized in table 8. One subject was excluded from the 0.50mg assay due to an incorrect testosterone solution dosing procedure.

Major pharmacokinetic endpoints

The pharmacokinetic parameters of total testosterone and free testosterone are summarized in tables 9 and 10.

Total testosterone

Three doses (0.25mg, 0.50mg, 0.75mg) produced the highest levels of total testosterone of 3.79ng/ml, 5.31ng/ml and 6.73ng/ml at 15.6min, 15.1min and 14.3min, respectively (FIG. 6).

C of Total Testosterone between three doses_{Maximum of}Is obviously different from (P)<0.0001). We found that between the three doses, the T of total testosterone_{Maximum of}There were no statistically significant differences. The AUC of total testosterone is also significantly different between the three doses (P)<0.0001) and exhibit a dose-dependent increase. The calculated half-life of total testosterone showed a significant difference between the 0.50mg dose and the 0.75mg dose (P ═ 0.125).

Free testosterone

The peak levels of free testosterone during the three doses were 0.021ng/mL, 0.032ng/mL, and 0.043ng/mL at 15.6min, 14.4min, and 12.8min, respectively (FIG. 7). Between the three doses, C for free testosterone_{Maximum of}In terms of this, there is a significant difference (P)<0.0001). Between the three doses, for free testosterone T_{Maximum of}In other words, there were no statistically significant differences. The free testosterone AUC was statistically significantly different between the three doses and increased dose-dependently. The difference between free testosterone AUC of 0.25mg and 0.50mg and 0.25mg and 0.75mg has a P value<0.0001, and the difference between 0.50mg and 0.75mg is significant (P)<0.01). There was no statistically significant difference in the calculated half-life of free testosterone between the three doses. Baseline levels of total and free testosterone were reached at 150min for all doses.

Bioavailability of

To determine the absolute percentage of sublingual testosterone dose absorbed in the systemic circulation, the fraction of absorbed testosterone needs to be calculated from a formula also used for post-intravenous AUC calculation. Since we have no intravenous standard, we use the 0.25mg dose as a reference value. Therefore, the bioavailability of 0.25mg was set as 100%, and was calculated as 69% (or 0.34mg), and 58% (or 0.43mg) for 0.50mg and 0.75 mg. The bioavailability of sublingual testosterone administration decreases with increasing dose.

Fraction of free

Our analysis showed a statistically significant effect of drug dose on free fraction of testosterone (i.e. ratio of free testosterone to total testosterone) during the t-4 min to t-30 min measurements (P-0.002). Between the 0.25mg dose and the 0.50mg dose and between the 0.25mg dose and the 0.75mg dose, but not between the 0.50mg dose and the 0.75mg dose, we also found C during t-4 min to t-30 min_{Maximum of}Statistically significant difference (P ═ 0.381) (fig. 8).

As described above, we expected to find a relationship between circulating SHBG and the increase in free level and free fraction of testosterone induced by different doses of sublingual testosterone. Furthermore, our experimental procedures produced no statistically significant changes in SHBG and albumin levels between and on the day of the trial (data not shown).

In our study population, we found that circulating SHBG levels varied widely between subjects. Baseline SHBG levels (log transformed) correlate with total testosterone levels (t ═ 20 min): for a dose of 0.25mg, 0.50mg, 0.75mg, r-732, p <.0002, respectively; r 930, p 001 and r 894, p 001. Baseline SHBG levels (log-transformed) were inversely correlated with free testosterone levels (t ═ 20 min): for a dose of 0.25mg, 0.50mg, 0.75mg, r- · 702, p <. 003; r-849, p 001 and r-798, p 001. We observed a stronger correlation for the free fraction level and SHBG level; for a dose of 0.25mg, 0.50mg, 0.75mg, r-947, p <.001, respectively, at t ═ 20; r-938, p 001 and r-944, p 001.

Because of this large difference between subjects, we subdivided the subjects into two groups based on median segmentation of baseline SHBG levels. The low SHBG group had a mean SHBG baseline level of 44nmol/L (+ -11), while the high SHBG group had a mean level of 183nmol/L (+ -141).

Total testosterone

In subjects with low SHBG, the three doses produced the highest levels of total testosterone of 3.18ng/ml, 3.93ng/m and 4.73ng/ml, respectively, 20min after dosing. In subjects with high SHBG, the highest levels of total testosterone after three doses of sublingual testosterone administration were 5.00ng/ml, 7.08ng/m and 9.04 ng/ml. Between groups, total testosterone levels were statistically different in 0.25mg and 0.50mg doses for t 10min up to t 30min and in 0.75mg doses for 6min up to 30min after administration.

Free testosterone

In subjects with low SHBG, the three doses produced the highest levels of free testosterone of 0.026ng/ml, 0.039ng/m and 0.048ng/ml, respectively, 20min after dosing. In subjects with high SHBG, the highest levels of free testosterone after administration of three doses of sublingual testosterone were 0.018ng/ml, 0.026ng/m and 0.034 ng/ml. All differences were statistically different between groups except for the level of free testosterone at 4min and 20min post-dose in the 0.25mg dose and at 4min and 10min post-dose in the 0.75mg dose.

Our analysis showed that the low SHBG group overall had a significantly higher level of free fraction compared to the high SHBG group (P ═ 0.007). Analysis revealed statistically significant group x drug effects for the difference between 0.25mg and 0.75mg (P ═ 0.012) and between 0.25mg and 0.50mg (P ═ 0.031) (see fig. 9). As shown in figure 9, statistically significant differences between different doses of sublingual testosterone were found in the low SHBG group.

Second order pharmacokinetic endpoint

Peak levels of DHT of 0.285ng/mL, 0.404ng/mL and 0.465ng/mL were achieved at 27.5min, 28.0min and 27.5min, respectively (Table 10).

The maximum difference between the three doses was not significant. 0.25mg and 0.50mg and 0.25mg and 0.75mg of C_{Maximum of}The difference between them is significant (P)<0.0001), and 0.50mg and 0.75mg of C_{Maximum of}The difference between them was statistically significant (P ═ 0.0310). There was no difference in the mean residence time of the three sublingual doses. In three kindsThe AUC was statistically significantly different between doses and increased dose-dependent.

The differences between AUC of 0.25mg and 0.50mg and 0.25mg and 0.75mg were statistically significant (P <0.0001), while the difference between 0.50mg and 0.75mg was significant (P ═ 0.0208). There was no statistically significant difference in the calculated half-life of DHT between the three doses. Return to DHT baseline levels occurred within 180min for all doses (fig. 10).

Increasing doses of sublingual testosterone did not appear to affect the 3 α -diol-G concentration as measured at t-0, t-60, t-120, and t-230. Between the three doses, C_{Maximum of}And AUC differences were not statistically significant. E₂Levels did not change between three doses of sublingual testosterone and were not significantly increased compared to baseline at t 60min and t 230min (data not shown).

Three doses of sublingual testosterone were well tolerated.

Discussion of the related Art

Our results show that there is a rapid and dramatic increase in total and free testosterone levels following sublingual administration of each of the three doses of testosterone; peak at 15 min. Serum levels of total and free testosterone decreased rapidly to reach baseline levels before 2.5h, consistent with our previous studies (Davison et al, 2005; Tuiten et al, 2000) and with the reported pharmacokinetic profile after ingestion of testosterone (Davison et al, 2005).

Total testosterone C after administration of 0.50mg sublingual testosterone_{Maximum of}Shows a C similar to that reported by Tuiten et al_{Maximum of}Uniformity of (Tuiten et al, 2000). Furthermore, in this study, C of total testosterone was achieved_{Maximum of}Time of day showed disagreement with the data from Tuiten et al and the study from Salehian et al, which administered 2.5mg and 5.0mg of sublingual testosterone (Salehian et al, 1995).

DHT levels showed a significant dose-dependent increase, reaching peak levels within 30min and returning to baseline levels within 3 h. DHT is metabolized to 3 α -diol-G, so an increase in 3 α -diol-G levels after sublingual testosterone administration is expected. However, no dose-dependent effect of sublingual testosterone on the concentration of 3 α -diol-G was found.

According to the SHBG saturation threshold hypothesis of van der Made et al (van der Made et al, 2009), the increased influx of testosterone into the body will occupy the SHBG binding site. Free (non-SHBG-bound) testosterone and then the free fraction will increase when the majority of the binding sites are occupied, and thus a behavioral effect is likely to be caused by genomic mechanisms after about 4h (Bos et al, 2011).

The results of this study show a dose-dependent significant increase in free testosterone levels and total testosterone levels, as reflected by the free fraction of testosterone. However, the difference in free fraction of testosterone between the 0.50mg condition and the 0.75mg condition did not reach statistical significance. Interestingly, T is in both free and total testosterone_{Maximum of}In the neighborhood, six women in the 0.75mg condition had lower levels of free fraction compared to the 0.50mg condition. It is not clear whether this is the result of differences in drug absorption or of large differences in SHBG levels between subjects (which may have affected the results). Moreover, it is also possible that the number of subjects may be too small to detect a significant increase in the level of free fraction between the two doses.

Testosterone has a high affinity for SHBG and slowly dissociates from SHBG. Free testosterone metabolizes rapidly (t)_1/210min), indicating the importance of SHBG binding and dissociative capacity, indicating that SHBG is a major determinant of free fraction balance. Figure 4 shows the free fraction levels of subjects with high and low SHBG levels. In the low SHBG group we observed an increase in sublingual testosterone free fraction caused by increasing doses of sublingual testosterone, however this was not found in women with high SHBG. These results confirm the hypothesis of van der Made et al (van der Made et al, 2009) that absorbed testosterone binds SHBG with limited capacity, and that free testosterone and free fraction increase only when this binding capacity is saturated.

According to van der Made, the increase in free fraction may be responsible for the behavioral effects observed after 3.5h to 4 h. However, in this study we measured free testosterone levels directly (using LC/MSMS) and we found that free testosterone levels were dose-dependent increasing in both SHBG groups, whereas the free fraction showed no dose-dependent increase. We therefore proposed adjustments to the SHBG saturation threshold hypothesis postulated by van der Made et al (van der Made et al, 2009); it was demonstrated that SHBG levels affect the percentage of free fraction of testosterone (and the maximum concentration of free testosterone), however, the increase in free testosterone levels appeared to be relatively less dependent on circulating SHBG levels after administration of the dose of sublingual testosterone used. Further studies were needed to investigate whether free testosterone levels or free fraction levels are responsible for the observed behavioral effects as described by van der Made et al.

The bioavailability data show that sublingual testosterone absorption decreases with increasing dose and is 69% and 58% for the 0.50 dose and 0.75 dose, respectively, when the 0.25mg condition is used as the reference value (100%). These data indicate the limit of the total amount of testosterone absorbed. The volume of sublingual testosterone solution is greater in higher dose conditions compared to lower doses. These increased volumes may affect absorption over a limited surface area in the mouth.

In this study, we did not consider the periodic and diurnal changes in testosterone. It is well known that testosterone levels are highest during the ovulatory and mid-luteal phases of the menstrual cycle, and lowest during the early follicular phase and late luteal phase (Judd and Yen, 1973; Rothman et al, 2011; Salonia et al, 2008). In this study, the blood samples were taken without taking into account the menstrual cycle. However, in this study nearly 60% of women use some form of hormonal contraceptive (compound oral contraceptive, compound contraceptive pessary), which is known to inhibit ovulation (Bancroft et al, 1991; Mulders and Dieben, 2001). Furthermore, we assume that the doses used for this study largely eliminated the effects of naturally occurring relatively minor periodic and diurnal variations in testosterone. Moreover, in a recent study by Branstein et al, SHBG levels in 161 women remained relatively stable throughout the menstrual cycle. They found a relatively small increase in testosterone levels in the mid-cycle compared to the overall change and showed that the described reference range can be applied regardless of which day of the menstrual cycle they were in (branstein et al, 2011). Therefore, a dose-dependent increase in total testosterone levels and free testosterone levels is therefore less likely to be biased by the periodic and diurnal variations of testosterone.

Other routes similar to the sublingual route of testosterone administration may also be investigated. However, the intramuscular and transdermal routes are not suitable for the immediate uptake and rapid return to baseline levels of testosterone desired, as both routes result in gradual systemic uptake and prolonged higher plasma levels after administration by these routes. Oral administration is not possible at all because unmodified testosterone will not reach the systemic circulation due to a very large first pass effect. For alternative routes to sublingual access with very rapid uptake and rapid return to testosterone baseline, pulmonary and nasal delivery may be used, in which case appropriate and convenient dosage forms need to be developed for them.

In summary, these three doses of testosterone are rapidly absorbed by the sublingual route and are rapidly metabolized without the presence of DHT and E₂Is continuously increasing. These data indicate the presence of SHBG thresholds, which affect the increase in the level of free fraction.

Reference to the literature

1.Aleman,A.,Bronk,E.,Kessels,R.P.,Koppeschaar,H.P.,van Honk,J.,2004.A single administration of testosterone improves visuospatial ability in young women.Psychoneuroendocrinology.29,612-7.

2.Auger,A.P.,2004.Steroid receptor control of reproductive behavior.Hormones and behavior.45,168-72.

3.Bancroft,J.,Sherwin,B.B.,Alexander,G.M.,Davidson,D.W.,Walker,

A.,1991.Oral contraceptives,androgens,and the sexuality of young women:II.The role of androgens.Archives of sexual behavior.20,121-35.

4.Bos,P.A.,Terburg,D.,van Honk,J.,2010.Testosterone decreases trust in socially naive humans.Proceedings of the National Academy of Sciences of the United States of America.107,9991-5.

5.Bos,P.A.,Panksepp,J.,Bluthe,R.M.,Honk,J.V.,2011.Acute effects of steroid hormones and neuropeptides on human social-emotional behavior:A review of single administration studies.Front.Neuroendocrinol.

6.Braunstein,G.D.,Reitz,R.E.,Buch,A.,Schnell,D.,Caulfield,M.P.,2011.Testosterone Reference Ranges in Normally Cycling Healthy Premenopausal Women.J.Sex.Med.

7.Brewster,M.E.,Estes,K.S.,Loftsson,T.,Perchalski,R.,Derendorf,H.,Mullersman,G.,Bodor,N.,1988.Improved delivery through biological membranes.XXXL:Solubilization and stabilization of an estradiol chemical delivery system by modified beta-cyclodextrins.Journal of pharmaceutical sciences.77,981-5.

8.Davison,S.,Thipphawong,J.,Blanchard,J.,Liu,K.,Morishige,R.,Gonda,I.,Okikawa,J.,Adams,J.,Evans,A.,Otulana,B.,Davis,S.,2005.Pharmacokinetics and acute safety of inhaled testosterone in postmenopausal women.Journal of clinical pharmacology.45,177-84.

9.Eisenegger,C.,Naef,M.,Snozzi,R.,Heinrichs,M.,Fehr,E.,2010.Prejudice and truth about the effect of testosterone on human bargaining behaviour.Nature.463,356-9.

10.Hermans,E.J.,Putman,P.,van Honk,J.,2006.Testosterone administration reduces empathetic behavior:a facial mimicry study.Psychoneuroendocrinology.31,859-66.

11.Hermans,E.J.,Ramsey,N.F.,van Honk,J.,2008.Exogenous testosterone enhances responsiveness to social threat in the neural circuitry of social aggression in humans.Biological psychiatry.63,263-70.

12.Hermans,E.J.,Putman,P.,Baas,J.M.,Gecks,N.M.,Kenemans,J.L.,van Honk,J.,2007.Exogenous testosterone attenuates the integrated central stress response in healthy young women.Psychoneuroendocrinology.32,1052-61.

13.Hull,E.M.,Dominguez,J.M.,2007.Sexual behavior in male rodents.Hormones and behavior.52,45-55.

14.Judd,H.L.,Yen,S.S.C.,1973.Serum Androstenedione and Testosterone Levels During Menstrual-Cycle.J.Clin.Endocrinol.Metab.36,475-481.

15.Labrie,F.,Belanger,A.,Belanger,P.,Berube,R.,Martel,C.,Cusan,L.,Gomez,J.,Candas,B.,Castiel,I.,Chaussade,V.,Deloche,C.,Leclaire,J.,2006.Androgen glucuronides,instead of testosterone,as the new markers of androgenic activity in women.The Journal of steroid biochemistry and molecular biology.99,182-8.

16.Mendel,C.M.,1989.The free hormone hypothesis:a physiologically based mathematical model.Endocr.Rev.10,232-274.

17.Miller,K.K.,Rosner,W.,Lee,H.,Hier,J.,Sesmilo,G.,Schoenfeld,D.,Neubauer,G.,Klibanski,A.,2004.Measurement of free testosterone in normal women and women with androgen deficiency:comparison of methods.The Journal of clinical endocrinology and metabolism.89,525-33.

18.Mulders,T.M.T.,Dieben,T.O.M.,2001.Use of the novel combined contraceptive vaginal ring NuvaRing for ovulation inhibition.Fertil.Steril.75,865-870.

19.Postma,A.,Meyer,G.,Tuiten,A.,van Honk,J.,Kessels,R.P.,Thijssen,J.,2000.Effects of testosterone administration on selective aspects of object-location memory in healthy young women.Psychoneuroendocrinology.25,563-75.

20.Rothman,M.S.,Carlson,N.E.,Xu,M.,Wang,C.,Swerdloff,R.,Lee,P.,Goh,V.H.,Ridgway,E.C.,Wierman,M.E.,2011.Reexamination of testosterone,dihydrotestosterone,estradiol and estrone levels across the menstrual cycle and in postmenopausal women measured by liquid chromatography-tandem mass spectrometry.Steroids.76,177-82.

21.Salehian,B.,Wang,C.,Alexander,G.,Davidson,T.,McDonald,V.,Berman,N.,Dudley,R.E.,Ziel,F.,Swerdloff,R.S.,1995.Pharmacokinetics,bioefficacy,and safety of sublingual testosterone cyclodextrin in hypogonadal men:comparison to testosterone enanthate--a clinical research center study.The Journal of clinical endocrinology and metabolism.80,3567-75.

22.Salonia,A.,Pontillo,M.,Nappi,R.E.,Zanni,G.,Fabbri,F.,Scavini,M.,Daverio,R.,Gallina,A.,Rigatti,P.,Bosi,E.,Bonini,P.A.,Montorsi,F.,2008.Menstrual cycle-related changes in circulating androgens in healthy women with self-reported normal sexual function.The journal of sexual medicine.5,854-63.

23.Schutter,D.J.,van Honk,J.,2004.Decoupling of midfrontal delta-beta oscillations after testosterone administration.Int J Psychophysiol.53,71-3.

24.Sherwin,B.B.,2002.Randomized clinical trials of combined estrogen-androgen preparations:effects on sexual functioning.Fertil.Steril.77,S49-S54.

25.Shifren,J.L.,Braunstein,G.D.,Simon,J.A.,Casson,P.R.,Buster,J.E.,Redmond,G.P.,Burki,R.E.,Ginsburg,E.S.,Rosen,R.C.,Leiblum,S.R.,Caramelli,K.E.,Mazer,N.A.,Jones,K.P.,Daugherty,C.A.,2000.Transdermal testosterone treatment in women with impaired sexual function after oophorectomy.N.Engl.J.Med.343,682-688.

26.Simon,J.,Braunstein,G.,Nachtigall,L.,Utian,W.,Katz,M.,Miller,S.,Waldbaum,A.,Bouchard,C.,Derzko,C.,Buch,A.,Rodenberg,C.,Lucas,J.,Davis,S.,2005.Testosterone patch increases sexual activity and desire in surgically menopausal women with hypoactive sexual desire disorder.J.Clin.Endocrinol.Metab.90,5226-5233.

27.Stuenkel,C.A.,Dudley,R.E.,Yen,S.S.,1991.Sublingual administration of testosterone-hydroxypropyl-beta-cyclodextrin inclusion complex simulates episodic androgen release in hypogonadal men.The Journal of clinical endocrinology and metabolism.72,1054-9.

28.Tuiten,A.,Van Honk,J.,Koppeschaar,H.,Bernaards,C.,Thijssen,J.,Verbaten,R.,2000.Time course of effects of testosterone administration on sexual arousal in women.Arch Gen Psychiatry.57,149-53；discussion 155-6.

29.Tuiten,A.,van Honk,J.,Verbaten,R.,Laan,E.,Everaerd,W.,Stam,H.,2002.Can sublingual testosterone increase subjective and physiological measures of laboratory-induced sexual arousalArchives of general psychiatry.59,465-6.

30.van der Made,F.,Bloemers,J.,Yassem,W.E.,Kleiverda,G.,Everaerd,W.,van Ham,D.,Olivier,B.,Koppeschaar,H.,Tuiten,A.,2009.The influence of testosterone combined with a PDE5-inhibitor on cognitive,affective,and physiological sexual functioning in women suffering from sexual dysfunction.The journal of sexual medicine.6,777-90.

31.van Honk,J.,Schutter,D.J.,2007.Testosterone reduces conscious detection of signals serving social correction:implications for antisocial behavior.Psychol Sci.18,663-7.

32.van Honk,J.,Peper,J.S.,Schutter,D.J.,2005.Testosterone reduces unconscious fear but not consciously experienced anxiety:implications for the disorders of fear and anxiety.Biological psychiatry.58,218-25.

33.van Honk,J.,Schutter,D.J.,Hermans,E.J.,Putman,P.,Tuiten,A.,Koppeschaar,H.,2004.Testosterone shifts the balance between sensitivity for punishment and reward in healthy young women.Psychoneuroendocrinology.29,937-43.

34.van Honk,J.,Tuiten,A.,Hermans,E.,Putman,P.,Koppeschaar,H.,Thijssen,J.,Verbaten,R.,van Doornen,L.,2001.A single administration of testosterone induces cardiac accelerative responses to angry faces in healthy young women.Behavioral neuroscience.115,238-42.

35.Zhang,H.,Zhang,J.,Streisand,J.B.,2002.Oral mucosal drug delivery:clinical pharmacokinetics and therapeutic applications.Clinical pharmacokinetics.41,661-80.

TABLE 7

TABLE 8

Positive-negative values refer to the mean. + -. SD. To convert total testosterone to nanomole/liter, 3.467 was multiplied; to convert free testosterone to picomoles/liter, multiply 3467; to convert the total DHT to nanomole/liter, multiply by 3.44. To convert 3 α -diol-G to nanomole/liter, multiply by 2.13.

All baseline levels are the mean of placebo, 0.25mg, 0.50mg, 0.75mg pre-dose levels.

^aThe sum of the percentages is less than 100% due to rounding off of the numbers.

^bMeasured in only 11 subjects; 5 subjects had values below LLOQ.

^cMeasured in only 15 subjects; 1 subject had a value below LLOQ.

Table 9.

^aTotal testosterone normally ranges from 0.14 to 0.66ng/mL (Davison et al, 2005).

^bFree testosterone normally ranges from 0.00072 to 0.0036ng/mL (Davison et al, 2005).

To convert total testosterone to nanomole/liter, 3.467 was multiplied; to convert free testosterone to picomoles/liter, 3467 was multiplied.

Mean residence time of MRT

Mean. + -. SD

Geometric mean (% CV)

Table 10.

DHT reference range ═ 0.29ng/mL (Davison et al, 2005)

To convert the total DHT to nanomole/liter, multiply by 3.44.

Mean. + -. SD

Geometric mean (% CV)

Example 7 development of buspirone core formulations

Formulations of buspirone cores were based on 50mg of sildenafil core. To develop the buspirone hydrochloride core, the same excipients and a similar "direct compression" manufacturing process were used. This formulation combines a water-insoluble filler (anhydrous dibasic calcium phosphate) with a water-insoluble binder (microcrystalline cellulose) and a small amount of superdisintegrant (sodium croscarmellose). The formulation is designed to provide sustained stress relaxation of the core and rupture of the barrier coating (after water has entered through the barrier coating), as well as rapid release of buspirone hydrochloride (after rupture of the coating).

The "direct compression" manufacturing process was used and direct compression multi-grades of anhydrous dibasic calcium phosphate (a-Tab, manufactured by Innophos) and microcrystalline cellulose (Avicel PH-200, manufactured by FMC Biopolymer) were selected to provide good flow properties and the ability to form hard tablets.

Formulation of 10mg buspirone hydrochloride core

The cores produced using this formulation and blending process had good physical properties, good content uniformity and rapidly disintegrated (less than 1 minute) allowing complete dissolution of buspirone hydrochloride in 10 minutes (using USP apparatus 3, 250ml of pH 4.5 sodium acetate buffer and 20 drops/minute). The test results are summarized in tables 11-14 below.

TABLE 11

Physical properties of 10mg buspirone hydrochloride core

TABLE 12

Buspirone hydrochloride dissolution from 10mg uncoated cores

Development of barrier coatings for buspirone cores

Barrier coating formulations and processes have been developed in multi-well pan coating machines. The coating is designed to release the API 120 to 180 minutes after the start of the in vitro dissolution test. A water-insoluble coating (ethylcellulose 20cps [ ethylcellulose 20]) in combination with microcrystalline cellulose [ Avicel PH-105 ])) allows controlled water ingress to cause gradual stress relaxation of the inner core and ultimately rupture of the insoluble coating in a PH-independent manner.

For the buspirone hydrochloride core, the same coating suspension and coating process as for the sildenafil core was used.

Watch 13

Formulation of barrier coating suspension

The experimental pan load of 10mg buspirone hydrochloride core was coated to determine the amount of barrier coating required to provide a delayed release between 120 and 180 minutes and to determine the effect of the heat treatment (curing) step after applying the barrier coating.

The selected samples were dried in a laboratory oven at 60 ℃ for 15 hours and retested to determine the effect of the heat treatment. The results are summarized in table 14.

TABLE 14

Time to rupture of 10mg buspirone hydrochloride barrier coated tablet samples before and after heat treatment in a laboratory oven

The results show that to achieve a break time of 120 to 180 minutes after heat treatment, a coating weight of about 44mg is required and the heat treatment step increases the average break time by about 20 minutes.

Another pan loading of 10mg buspirone hydrochloride core was barrier coated to investigate the heat treatment in the coated pan.

Watch 15

Time to rupture of 10mg buspirone hydrochloride barrier coated tablets before and after heat treatment in the coating pan

# 12 tablets tested

Batch number 2112/60

The results were similar to the initial coating trials, which indicated that to achieve a target burst time of 120 to 180 minutes, approximately 44mg of coating was required, combined with a heat treatment in the coating pan for 60 minutes. Heating for 90 minutes did not produce a significant change in mean time to break, indicating that the "curing" process was complete after 60 minutes.

In summary, it was found that a barrier coat weight of between 35mg to 50mg per core, preferably about 44mg per core, is necessary to provide the time delay required before the buspirone hydrochloride core ruptures. It appears that a heating (curing) step is required to stabilize the coating to prevent variations in break time when storing the coated tablets. The heating (curing) step was found to increase the mean breaking time of the tablets by about 20 minutes to 30 minutes (compare the coated tablets before and after heat treatment).

Example 8 clinical study

A randomized, cross-control study comparing the pharmacokinetic distribution of two combination products (sublingual solution with encapsulated tablets with combination tablets containing testosterone and sildenafil citrate) in premenopausal women. A total of 12 subjects received formulation 1(F1) in random order: testosterone (0.5mg) administered sublingually as a solution, a packaged tablet containing 50mg sildenafil as sildenafil citrate after 2.5 hours, or formulation 2 (F2): a fixed combination, a tablet consisting of an inner core component of 50mg of sildenafil citrate as sildenafil citrate, coated with a polymer coating designed to release sildenafil citrate 2.5 hours after ingestion of the tablet. The coated sildenafil core tablet is a film coated with an additional, immediately soluble, polymeric testosterone coating that releases 0.5mg testosterone sublingually within 2 minutes.

The primary objective of this study was to compare the pharmacokinetic profiles of sildenafil citrate after sublingual testosterone cyclodextrin as an encapsulated tablet (F1) with the administration of testosterone and sildenafil citrate as a single tablet designed to release the ingredients over a specific time frame (F2).

The second objective was to study the time frame for sublingual dissolution of the testosterone coating in the combined tablets.

Materials and methods

EDTA whole blood samples of 12 subjects receiving pharmaceutical dosage formulation 1(F1) and formulation 2(F2) in random order were collected pre-dose (-10 minutes) and at 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes, 135 minutes, 145 minutes, 165 minutes, 180 minutes, 195 minutes, 210 minutes, 225 minutes, 240 minutes, 270 minutes, 300 minutes, 330 minutes, 360 minutes, 390 minutes, 450 minutes, 570 minutes, 690 minutes, 810 minutes, 930 minutes, and 1590 minutes post-dose.

Blood samples for testosterone (T), Free Testosterone (FT) and Dihydrotestosterone (DHT) analysis were taken before dosing and at 5min, 10min, 15min, 20min, 25 min, 30min, 60min, 90 min, 120 min, 145 min, 160 min, 240 min and 1590 min (14 time points total) after dosing. The concentrations of testosterone, dihydrotestosterone, and free testosterone were determined as described in example 6.

For F1, blood samples for analysis of sildenafil (S) and N-desmethyl sildenafil (NDS) were collected at 145 minutes, 165 minutes, 180 minutes, 195 minutes, 210 minutes, 225 minutes, 240 minutes, 270 minutes, 300 minutes, 330 minutes, 360 minutes, 390 minutes, 450 minutes, 570 minutes, 690 minutes, 810 minutes, 930 minutes and 1590 minutes (18 time points in total) post-dose, while for F2, blood samples for analysis of sildenafil (S) and N-desmethyl sildenafil (NDS) were collected before and 10 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes, 135 minutes, 145 minutes, 165 minutes, 180 minutes, 195 minutes, 210 minutes, 225 minutes, 240 minutes, 270 minutes, 300 minutes, 330 minutes, 360 minutes, 390 minutes, 450 minutes, 570 minutes, 690 minutes, 810 minutes, 930 minutes and 1590 minutes post-dose.

The concentrations of sildenafil (S) and N-desmethylsildenafil (NDS) were determined by HPLC-MS/MS as described below.

Human plasma samples were vortexed and 0.5mL of the sample was transferred to a clean tube to which 20 μ L of internal standard solution in methanol (10ng/mL) was added and vortexed. Then, 4mL of methyl tert-butyl ether (MTBE) was added, the tube was capped and shaken for 10 minutes, and then centrifuged at 2000rcf for 5 minutes. The tube was placed in a quick freezer (snap freezer) and the bottom aqueous layer was frozen. The supernatant was transferred to a clean tube and evaporated to dryness under a stream of nitrogen. Redissolving the solvent (50/50 containing 0.1% acetic acid: MeOH/H) with 200. mu.L₂O) the residue was redissolved, transferred to a glass autosampler vial and then placed on an autosampler pan. 7 μ L of injection was prepared for HPLC-MS/MS analysis.

HPLC-MS/MS measurements were performed using the following equipment:

an analysis system: applicable biological system/MDSSCIEXAPI-4000 triple quadrupole mass spectrometer with analysis software

Mode (2): positive multiplex reaction monitoring

Interface: ion spray (turbo spray)

HPLC system: shimadzu Co-sense system

HPLC column: phenomenex Kinetex, C18 size 100X 2.1mm, particle size 2.6 μm

Measurement (M/z):

sildenafil 475/283

N-demethylsildenafil 461/283

D₈-N-demethylsildenafil 469/283

Pharmacokinetic analysis

The software used for pharmacokinetic analysis was Watson 7.2Bioanalytical LIMS software (Thermo Electron Corporation-Philadelphia-USA).

Cmax and tmax are read from the observations. Half-life was calculated from unweighted linear regression of logarithmically transformed data determined at the exclusion phase of pharmacokinetic distribution. The area under the curve (0 to final) was determined as the area under the concentration versus time curve from the first time point to the last time point with measurable drug concentration using a linear/log-linear trapezoidal model. The AUC (0 to ∞) from the time point when the last measurable drug concentration (Cp) occurred to time infinity was determined by extrapolation. This was done by dividing the concentration observed at the last time point by the elimination rate constant determined using linear regression of the Cp versus time data (standard extrapolation techniques). The T delay (Tlag) was determined as the first time point with a measurable concentration.

Results

A total of 12 subjects received formulation (F1) and formulation (F2) in random order.

TABLE 16 pharmacokinetic parameters of testosterone (T), Free Testosterone (FT) and Dihydrotestosterone (DHT), sildenafil (S) and N-desmethylsildenafil (NDS).

Pharmacokinetic parameters of Testosterone

Pharmacokinetic parameters of free testosterone

Pharmacokinetic parameters of dihydrotestosterone

Pharmacokinetic parameters of sildenafil

Pharmacokinetic parameters of N-desmethylsildenafil

Fig. 12 and 13 show mean concentration-time curves of testosterone and free testosterone from plasma measured after oral administration of a single dose of testosterone (0.5mg) using the F1 and F2 dosing methods in healthy pre-menopausal female subjects.

Figure 14 shows the mean concentration-time profiles of sildenafil from plasma measured after oral administration of a single dose of sildenafil (50mg) using the F1 and F2 dosing regimens in healthy premenopausal female subjects. Since testosterone is endogenous in plasma, for all calculations, the pre-dose concentrations were subtracted from the concentrations determined after dosing. The calculated concentrations were used for PK calculations. One subject was excluded from PK calculations for the F2 dosed group using testosterone, dihydrotestosterone and free testosterone analysis. A further subject was not included in the free testosterone PK calculation for the F1 dosed group.

Pharmacokinetic results show that testosterone is rapidly absorbed, with tmax in the range between 10 and 20 minutes and a mean half-life of about 37 minutes. The free testosterone results show comparable images to the testosterone results. However, dihydrotestosterone has a tmax and half-life that is later than testosterone. It should be noted that the mean AUC for testosterone, dihydrotestosterone and free testosterone was higher with F2 compared to F1 administration.

Sildenafil exposure was prolonged and did not begin until about three hours after the first dose. The mean tmax for sildenafil was approximately 4 hours with F1, and just over 3 hours with F2. N-demethylsildenafil follows the same pattern as sildenafil, i.e. tmax which is only a few minutes later and comparable half-life. It should be noted that the mean AUC for sildenafil and desmethylsildenafil was higher with F1 compared to F2.

The tmax-tmax delay for sildenafil administered with F2 was 3.10-2.74-0.36 h (see table 16), indicating that the maximum concentration of sildenafil was reached soon after the core of the dual drug delivery device was ruptured.

Example 9

Cores having the compositions as shown in Table 17 were coated with 21.5mg of ethylcellulose/Avicel (1:1w/w) coating. In vitro dissolution test experiments were performed using USP dissolution apparatus No. II (Prolabo, Rowa techniek BV) at 50 rpm in 1000ml of medium (n ═ 6) at 30 ℃. The dissolution medium used was citrate buffer (pH 4.5). The amount of dissolved sildenafil was continuously determined by UV absorbance at a wavelength of 291 nm.

A representative example of dissolution of a single tablet is depicted in fig. 15.

TABLE 17 composition of nuclei

Material	Amount (mg/tablet)
		Sildenafil citrate	70.24
Microcrystalline cellulose (Avicel PH-200)	102.88
		Anhydrous calcium hydrogen phosphate (A-TAB)	102.88
Croscarmellose sodium (Ac-Di-Sol)	12.0
		Magnesium stearate (vegetable source)	12.0
Total of	300.0

Example 10

A representative example of dissolution experiments for a single tablet having a coated core with the composition shown in table 18 is depicted in fig. 16.

In vitro dissolution test experiments were performed using USP dissolution apparatus No. II (Prolabo, Rowa techniek BV) at 50 rpm in 1000ml of medium (n ═ 6) at 37 ℃. The dissolution medium used was citrate buffer, pH 4.5. The amount of dissolved sildenafil was continuously determined by UV absorbance at 291nm wavelength.

TABLE 18 composition of nuclei

Claims

1. A tablet for sublingual administration of an active ingredient, said tablet comprising a core, an outer coating on the outer surface of said core and optionally a separate coating separating said outer coating from said core, wherein said outer coating comprises a mixture of:

-steroid in an amount between 0.1mg and 10mg in amorphous form as active ingredient;

-a coating polymer in an amount between 0.25mg and 25mg, said coating polymer comprising a film forming ingredient selected from the group consisting of modified cellulose, povidone, polyacrylate, polymethacrylate and polymethylmethacrylate/ethyl ester;

cyclodextrin, polyvinylpyrrolidone, or a combination thereof in an amount between 0.25mg and 25mg,

-water in an amount between 0.0% w/w-10% w/w; and optionally

Sweeteners and/or flavors.

2. The tablet of claim 1, wherein the cyclodextrin, polyvinylpyrrolidone, or combination thereof is present in an amount between 0.5mg-12.5 mg.

3. The tablet according to claim 1, wherein said active ingredient for sublingual administration is present in an amount of between 0.2-5 mg.

4. The tablet according to claim 1, wherein the active ingredient is testosterone and/or dihydrotestosterone.

5. The tablet of claim 1, wherein the coating polymer is hydroxypropyl methylcellulose.

6. The tablet of claim 1, wherein the outer coating comprises:

between 1mg to 2mg hydroxypropyl methylcellulose 5 cps;

between 2mg to 3.5mg hydroxypropyl beta-cyclodextrin; and

between 0.1mg to 1mg of testosterone.

7. The tablet of claim 1, wherein the core comprises an additional active ingredient in a relative amount of between 0.1 to 60% w/w based on the total weight of the core.

8. The tablet of claim 1, wherein the separating coating separating the outer coating from the core is present, the separating coating comprising a hydrophobic polymer and a hydrophilic substance.

9. The tablet of claim 8, wherein the separating coating comprises the hydrophobic polymer and the hydrophilic substance in a mass ratio of between 1:5 and 5: 1.

10. The tablet of claim 8, wherein the separation coating comprises ethyl cellulose as the hydrophobic polymer.

11. The tablet of claim 8, wherein the separation coating comprises microcrystalline cellulose as the hydrophilic substance.

12. The tablet according to claim 7, wherein the tablet provides a time controlled immediate release of the additional active ingredient.

13. The tablet of claim 12, wherein the tablet provides immediate release of the additional active ingredient after 2 hours after administration of the tablet.

14. The tablet of claim 1, wherein the core comprises an additional active ingredient, cellulose, and a filler.

15. Tablet according to claim 14, wherein the core comprises 10-50% w/w microcrystalline cellulose, 20-70% w/w anhydrous dibasic calcium phosphate or calcium sulphate dehydrate as filler and lubricant, wherein the percentages are based on the total weight of the core.

16. Tablet according to claim 14, wherein the core comprises 10-50% w/w microcrystalline cellulose, 20-70% w/w anhydrous calcium hydrogen phosphate or calcium sulphate dehydrate as filler and 0.1-10% w/w magnesium stearate, wherein percentages are based on the total weight of the core.

17. The tablet of claim 15 or 16, wherein the core further comprises less than 6% by weight of croscarmellose sodium.

18. The tablet according to claim 7, wherein the core comprises 0.1 to 30% w/w of a PDE5 inhibitor or a 5-HT1a receptor agonist as the further active ingredient.